Kelch proteiinit lihastaudeissa ( katsaus 2014, Gupta, Beggs, jatkoa, fylogeneettinen puu ), KLHL, KBTBD, KLHDC alaperheet

Figure 2https://media.springernature.com/full/springer-static/image/art%3A10.1186%2F2044-5040-4-11/MediaObjects/13395_2014_Article_102_Fig2_HTML.jpg?as=webp

From: Kelch proteins: emerging roles in skeletal muscle development and diseases

Phylogenetic analysis showing relationships between human Kelch protein family members. (A) Phylogenetic tree of full-length amino acid sequences of human proteins were aligned. (B) Phylogenetic tree of amino acid sequences of Kelch domains. Phylogenetic trees were constructed by maximum-likelihood method using BLOSUM matrix in MEGA 6.06. Reference sequences used for alignments are indicated at right of each protein name. Blue highlighting indicates KBTBD subfamily members; green indicates

The Kelch Superfamily. (A) The Kelch family consists of 63 proteins that are subclassified in to KLHL, KBTBD and KLHDC subfamilies. (B) Structure of Kelch domain of rat KLHL41 (PDB code 2WOZ) comprising six repeats that form the complete Kelch domain. The structure was generated using PyMOL (http://www.pymol.org)
. (C) Prototype members of different subfamilies showing different domain organization.
 KLHL proteins have an N-terminal BTB/POZ, a BACK and C-terminal Kelch repeats.
 KBTBD proteins contain an N-terminal BTB domain and Kelch repeats. The BACK domain is normally absent in KBTBD proteins.
 KLHDC proteins lack both BTB/POZ and BACK domains and contain either Kelch repeats alone or with other domains such as transmembrane (for example, KLHDC7A), Glycine rich (for example, KLHDC10), or Lish and CTLH domains (for example, MKLN1).

Kelch proteiinit lihastaudeissa (2014 katsaus, V.A. Gupta, A.H. Beggs)

PÄIVITYSHAKU   KELCH proteins and skeletal muscle

https://pubmed.ncbi.nlm.nih.gov/?term=Kelch+proteins+and+Sceletal+muscle+

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067060/
  Skelet Muscle. 2014; 4: 11.

Published online 2014 Jun 1. doi: 10.1186/2044-5040-4-11

PMCID: PMC4067060

PMID: 24959344

(2014 katsaus)

Vandana A Gupta¹ and Alan H Beggs¹

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

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Abstract

Our understanding of genes that cause skeletal muscle disease has increased tremendously over the past three decades. Advances in approaches to genetics and genomics have aided in the identification of new pathogenic mechanisms in rare genetic disorders and have opened up new avenues for therapeutic interventions by identification of new molecular pathways in muscle disease. Recent studies have identified mutations of several Kelch proteins in skeletal muscle disorders. The Kelch superfamily is one of the largest evolutionary conserved gene families. The 66 known family members all possess a Kelch-repeat containing domain and are implicated in diverse biological functions. In skeletal muscle development, several Kelch family members regulate the processes of proliferation and/or differentiation resulting in normal functioning of mature muscles. Importantly, many Kelch proteins function as substrate-specific adaptors for Cullin E3 ubiquitin ligase (Cul3), a core component of the ubiquitin-proteasome system to regulate the protein turnover. This review discusses the emerging roles of Kelch proteins in skeletal muscle function and disease.

Keywords: Kelch, BTB, BACK, Nemaline myopathy, Dystrophy, Congenital myopathy, Cul3, Ubiquitination, Proteasome, Skeletal muscle, Proliferation, Differentiation

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Review

Skeletal muscle development is a highly coordinated process that involves the myogenesis and differentiation of primary myoblasts, and their integrated growth and development into a mature functional organ [1-4]. Consequently, mutations of a large number of proteins associated with development and/or maintenance of skeletal muscle result in disease states. Over the past three decades, tremendous progress has been made in elucidating the genetic basis of muscle diseases. Primary inherited diseases of skeletal muscle include the muscular dystrophies and the non-dystrophic congenital myopathies [5-8].
 Muscular dystrophies are characterized by myofiber degeneration with repeated rounds of regeneration that ultimately lead to an end-stage process typified by fibrosis and replacement by adipose tissue [9,10].
In contrast, non-dystrophic myopathies exhibit little necrotic or regenerative changes, but muscle biopsies often display characteristic structural changes such as central cores, nemaline rods, central nuclei, various intracytoplasmic inclusions, or fiber type disproportion, and so on [10,11]. Collectively, these diseases are both phenotypically and clinically heterogeneous.

 
Gene discovery in muscle diseases is currently skyrocketing due to the use of next-generation sequencing approaches [12-19]. The discovery of new genes is not only crucial for improving diagnostics for these highly heterogeneous muscular disorders, but also is critical for identifying new molecular pathways that may serve as potential therapeutic targets. Recent gene discoveries have identified mutations in Kelch protein genes as the cause of muscle diseases in humans [14,20-22]. Kelch proteins belong to the Kelch superfamily that consists of a large number of structurally and functionally diverse proteins characterized by the presence of a Kelch-repeat domain [23,24]. Kelch family members are involved in a number of cellular and molecular processes such as cell migration, cytoskeletal arrangement, regulation of cell morphology, protein degradation, and gene expression [25-31]. This review summarizes our emerging understanding of the various roles of Kelch proteins in skeletal muscle development and disease (Tables  1 and ​and22).

Table 1

Kelch family proteins in skeletal muscle development

Gene	Protein	Function	Expression
KLHL19	KLHL19, KEAP1	Oxidative stress and insulin signaling in muscle cells [32]	Ubiquitous [33]
KLHL31	KLHL31	Skeletal and cardiac muscle myogenesis [29,34]	Skeletal muscle, heart (low levels in brain, kidney, and liver) [29]
KLHL39	KLHL39, IVNS1ABP	Protection against drug-induced cardiomyopathy [35]	Ubiquitous [36]
KLHL40 (KBTBD5)	KLHL40	Skeletal muscle differentiation [14,37]	Skeletal muscle [14]
KLHL41 (KBTBD10 , KRP1)	KLHL41, Sarcosin	Skeletal muscle differentiation and myofibril assembly [22,38,39]	Skeletal muscle, lungs [22]
MKLN1	MKLN1, Muskelin	Muscle cell adhesion and extracellular communication [40]	Skeletal muscle, brain [40,41]
KLHDC1	KLHDC1	Muscle cell migration and differentiation [42,43]	Skeletal muscle [42]
KLHDC2	KLHDC2	Muscle cell migration and differentiation [42,43]	Skeletal muscle [42]

Table 2

Kelch family proteins in human diseases

Gene	Function	Expression
Neuromuscular diseases
KLHL1	Spinocerebellar ataxia type 8 [44]	Brain, prostate, small intestine, colon [44]
KLHL9	Distal myopathy [20]	Ubiquitous [20]
KLHL16 (GAN)	Giant axonal neuropathy [45]	Brain, skeletal muscle, heart, kidney, liver [46]
KLHL40 (KBTBD5)	Severe nemaline myopathy with fetal akinesia [14,37]	Skeletal muscle [14]
KLHL41 (KBTBD10)	Nemaline myopathy [22,38,39]	Skeletal muscle, lungs [22]
KBTBD13	Nemaline myopathy with cores [21]	Skeletal muscle, lungs, heart [21]
Cancer
KLHL6	Chronic lymphocytic leukemia [47]	Lymphocytes (unknown in other tissues) [48]
KLHL19 (KEAP1)	Pulmonary papillary adenocarcinoma [49]	Ubiquitous [50]
KLHL20	Prostate cancer progression [51]	Ubiquitous [52]
KLHL37 (ENC1)	Brain tumors [53]	Brain (unknown in other tissues) [54]
KLHDC8B	Hodgkin’s lymphoma [55]	Unknown

PMC full text:

Skelet Muscle. 2014; 4: 11. Published online 2014 Jun 1. doi: 10.1186/2044-5040-4-11 Copyright/LicenseRequest permission to reuse

KLHDC4 (16q24.2) ,biomerkitsijä syövässä

https://www.ncbi.nlm.nih.gov/gene/54758
Ilmentyy testiksessä ja imusolmukkeessa eniten . Koko: 463 a.a.

1. NM_001184854.2 → NP_001171783.1  kelch domain-containing protein 4 isoform 3
   See identical proteins and their annotated locations for NP_001171783.1
   
   

   ORIGIN      
           1 mgkkgkkekk grgaektaak mekkvskrsr keetflynel yvyntrkdtw tkvdipsppp
          61 rrcahqavvv pqgggqlwvf ggefaspnge qfyhykdlwv lhlatktweq vkstggpsgr
         121 sghrmvawkr qlilfggfhe strdyiyynd vyafnldtft wsklspsgtg ptprsgcqms
         181 vtpqggivvy ggyskqrvkk dvdkgtrhsd mfllkpedgr edkwvwtrmn psgvkptprs
         241 gfsvamapnh qtlffggvcd eeeeeslsge ffndlyfyda trnrwfegql kgpksekkkr
         301 rrgrkeepeg gsrpacggag tqgpvqlvke vvaedgtvvt ikqvltapgs agqprseded
         361 sleeagspap gpcprsnaml avkhgvlyvy ggmfeagdrq vtlsdlhcld lhrmeawkal
         421 vemdpetqew leetdseeds eevegaeggv ddedsgeesg aed

   
   

   Conserved Domains (3) summary

   sd00038
   Location:62 → 117

   Kelch; KELCH repeat [structural motif]

   pfam13415
   Location:129 → 181

   Kelch_3; Galactose oxidase, central domain

   pfam13418
   Location:173 → 229

   Kelch_4; Galactose oxidase, central domain

Related articles in PubMed

1. Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma. Lian YF, et al. PLoS One, 2016. PMID 27030985, Free PMC ArticleKelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0 .05="" and="" b="" classification="" expression="" had="" higher="" in="" klhdc4="" metastasis-free="" n="" npc="" overall="" patients="" poorer="" rates.="" staging="" survival="" total="" with=""> Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation,

colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.

Huntington Disease-Like 2 Anderson DG, et al. , 1993. PMID 20301701

A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Holmes SE, et al. Nat Genet, 2001 Dec. PMID 11694876

Hereditary Dystonia Overview Klein C, et al. , 1993. PMID 20301334

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins. Tomkins JE, et al. Proteomics, 2018 May. PMID 29513927, Free PMC Article

See all (19) citations in PubMed

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GeneRIFs: Gene References Into Functions

What's a GeneRIF? KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis.

KLHDC2 (14q21.3), LCP, HCLP1,HCLP-1

https://www.ncbi.nlm.nih.gov/gene/23588

Also known as

LCP; HCLP1; HCLP-1

Expression

Ubiquitous expression in thyroid (RPKM 22.9), kidney (RPKM 22.5) and 25 other tissues See more

Preferred Names

kelch domain-containing protein 2

Names

hepatocellular carcinoma-associated antigen 33

host cell factor homolog LCP

host cell factor-like protein 1

1.   mRNA and Protein(s)
2. NM_014315.3 → NP_055130.1  kelch domain-containing protein 2
   See identical proteins and their annotated locations for NP_055130.1
   

   ORIGIN      
           1 madgnedlra ddlpgpafes yesmelacpa ersghvavsd grhmfvwggy ksnqvrglyd
          61 fylpreelwi ynmetgrwkk integdvpps msgscavcvd rvlylfgghh srgntnkfym
         121 ldsrstdrvl qweridcqgi ppsskdklgv wvyknkliff ggygylpedk vlgtfefdet
         181 sfwnsshprg wndhvhildt etftwsqpit tgkapspraa hacatvgnrg fvfggryrda
         241 rmndlhylnl dtwewnelip qgicpvgrsw hsltpvssdh lflfggfttd kqplsdawty
         301 cisknewiqf nhpytekprl whtacasdeg evivfggcan nllvhhraah sneilifsvq
         361 pkslvrlsle avicfkemla nswnclpkhl lhsvnqrfgs nntsgs
   //

   Conserved Domains (3) summary

   sd00038
   Location:218 → 265

   Kelch; KELCH repeat [structural motif]

   pfam13415
   Location:279 → 326

   Kelch_3; Galactose oxidase, central domain

   cl26061
   Location:29 → 296

   PLN02193; nitrile-specifier protein

3. Differential subcellular localization and activity of kelch repeat proteins KLHDC1 and KLHDC2. Chin KT, et al. Mol Cell Biochem, 2007 Feb. PMID 16964437
4. Recognition of the Diglycine C-End Degron by CRL2^KLHDC2 Ubiquitin Ligase. Rusnac DV, et al. Mol Cell, 2018 Dec 6. PMID 30526872,
5. Inhibition of LZIP-mediated transcription through direct interaction with a novel host cell factor-like protein. Zhou HJ, et al. J Biol Chem, 2001 Aug 3. PMID 11384994
6. Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies. Wang Y, et al. J Immunol, 2002 Jul 15. PMID 12097419Autoantibodies are often detected in hepatocellular carcinoma (HCC), and these responses may represent recognition of tumor Ags that are associated with transformation events. The identities of these Ags, however, are less well known. Using serological analysis of recombinant cDNA expression libraries (SEREX) from four HCC patients, we identified 55 independent cDNA sequences potentially encoding HCC tumor Ags. Of these genes, 15 are novel. Two such proteins, HCA587 and HCA661, were predominantly detected in testis, but not in other normal tissues, except for a weak expression in normal pancreas. In addition to HCC, these two Ags can be found in cancers of other histological types. Therefore, they can be categorized as cancer-testis (CT) Ags. Two other Ags (HCA519 and HCA90) were highly overexpressed in HCC and also expressed in cancer cell lines of lung, prostate, and pancreas, but not in the respective normal tissues. Four other Ags were identified to be expressed in particular types of cancer cell lines (HCA520 in an ovarian cancer cell line, HCA59 and HCA67 in a colon cancer cell line, HCA58 in colon and ovarian cancer cell lines), but not in the normal tissue counterpart(s). In addition, abundant expression of complement inactivation factors was found in HCC. These results indicate a broad range expression of autoantigens in HCC patients. Our findings open an avenue for the study of autoantigens in the transformation, metastasis, and immune evasion in HCC.
7. Characterization of Cullin-box sequences that direct recruitment of Cul2-Rbx1 and Cul5-Rbx2 modules to Elongin BC-based ubiquitin ligases. Mahrour N, et al. J Biol Chem, 2008 Mar 21. PMID 18187417

See all (22) citations in PubMed

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KLHDC1, MST025, Suositeltu nimi: kelch domain-containing protein 1. (Koko: 406 a.a.)

https://www.ncbi.nlm.nih.gov/gene/122773
KLHCC1  ilmenee ovariossa ja kilpirauhasessa eniten.   Koko: 406 aminohappoa,

KLHDC1 kelch domain containing 1 [ Homo sapiens (human) ]

Official Symbol

KLHDC1

Official Full Name

kelch domain containing 1

Also known as

MST025

Expression

Ubiquitous expression in ovary (RPKM 2.8), thyroid (RPKM 2.6) and 25 other tissues See more

1. NM_172193.3 → NP_751943.1  kelch domain-containing protein 1
   See identical proteins and their annotated locations for NP_751943.1
   

   ORIGIN  ( 406  a.a.)      
           1 madsqlfcva eersghcavv dgnflyvwgg yvsiednevy lpndeiwtyd idsglwrmhl
          61 megelpasms gscgacingk lyifggyddk gysnrlyfvn lrtrdetyiw ekitdfegqp
         121 ptprdklscw vykdrliyfg gygcrrhsel qdcfdvhdas weeqifwgwh ndvhifdtkt
         181 qtwfqpeikg gvppqpraah tcavlgnkgy ifggrvlqtr mndlhylnld twtwsgriti
         241 ngespkhrsw htltpiaddk lflcgglsad niplsdgwih nvttncwkql thlpktrprl
         301 whtaclgken eimvfggskd dllaldtghc ndllifqtqp ysllrscldc igknsimles
         361 qisllppkll qqvlkkitfw aaanhreeqr vqkeetenky qwissn

   
    
   

   Conserved Domains (4) summary

   sd00038
   Location:13 → 65

   Kelch; KELCH repeat [structural motif]

   pfam13415
   Location:206 → 256

   Kelch_3; Galactose oxidase, central domain

   pfam13418
   Location:247 → 294

   Kelch_4; Galactose oxidase, central domain

   pfam13854
   Location:13 → 54

   Kelch_5; Kelch motif

1. Differential subcellular localization and activity of kelch repeat proteins KLHDC1 and KLHDC2. Chin KT, et al. Mol Cell Biochem, 2007 Feb. PMID 16964437 We have previously identified and characterized human KLHDC2/HCLP-1, a kelch repeat protein that interacts with and inhibits transcription factor LZIP. In this study, we identified and characterized a paralog of KLHDC2 called KLHDC1. KLHDC1 and KLHDC2 share about 50% identity at the level of amino acid sequence and both gene loci localize to human chromosome 14q21.3. This cluster of KLHDC1 and KLHDC2 genes is highly conserved in vertebrates ranging from pufferfish to human. Both genes are expressed highly in skeletal muscle, but weakly in various other tissues. While KLHDC2 was predominantly found in the nucleus, KLHDC1 is a cytoplasmic protein. Neither KLHDC1 nor KLHDC2 binds to actin. In addition, KLHDC1 was unable to inhibit LZIP/CREB3-mediated transcriptional activation. Thus, KLHDC1 and KLHDC2 have differential localization and activity in cultured mammalian cells.
2. Data show that KLHDC1 and KLHDC2 have differential localization and activity in cultured mammalian cells.
3.  Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding
   Author links open overlay panelFumihikoOkumura¹⁶
   YuhaFujiki^{1 et al.} https://doi.org/10.1016/j.isci.2020.100970

KBTBD14 = BTBD20 = CCIN(9p13.3) , kalisiini calicin

KBTBD12 (3q21.3) = KLHDC6, Ilmentyy sydämessä

https://www.ncbi.nlm.nih.gov/gene/166348
(ilmentyy sydämessä) , heart

Preferred Names

kelch repeat and BTB domain-containing protein 12

Names

kelch domain containing 6

kelch domain-containing protein 6

kelch repeat and BTB (POZ) domain containing 12

1. NM_001370224.1 → NP_001357153.1  kelch repeat and BTB domain-containing protein 12

   ORIGIN      
           1 meckiegkek yqhslnllnk iqnmkelaem idvvltaege kfpchrlvla afspyfkamf
          61 tcgllecnqr evilyditae svsvllnymy naaleinnan vqtvamaayf mqmeevfsvc
         121 qkymmdhmda snclgiyyfa kqigaedlsd rskkylyqhf aevslheeil eievhqfltl
         181 iksddlnisr eesildlvlr wvnhnkelrt vhlvellkqv rlelvnpsfl rqalrrntml
         241 lcdadcvdii qnafkaiktp qqhslnlryg mettslllci gnnssgirsr hrsygdasfc
         301 ydpvsrktyf isspkygegl gtvctgvvme nntiivagea sasklsrqkn knveiyryhd
         361 rgnqfweklc taefrelyal gsihndlyvi ggqmkiknqy litncvdkys verdnwkrvs
         421 plplqlacha vvtvnnklyv iggwtpqmdl pdeepdrlsn kllqydpsqd qwsvrapmky
         481 skyrfstavv nseiyvlggi gcvgqdkgqv rkcldvveiy npdgdfwreg ppmpspllsl
         541 rtnstnagav dgklyvcggf hgadrhevis keileldpwe nqwnvvainv lmhdsydvcl
         601 varmnprdli pppsdlveeg neh

   Conserved Domains (4) summary

   PHA03098
   Location:29 → 586

   PHA03098; kelch-like protein; Provisional

   sd00038
   Location:375 → 422

   Kelch; KELCH repeat [structural motif]

   cd18276
   Location:10 → 136

   BTB_POZ_KBTBD12; BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain found in Kelch repeat and BTB domain-containing protein 12 (KBTBD12)

   cd18485
   Location:128 → 227

   BACK_KBTBD12; BACK (BTB and C-terminal Kelch) domain found in Kelch repeat and BTB domain-containing protein 12 (KBTBD12)

Related articles in PubMed

KBTB (8p23.3), KLHDC7C , Kr. myel.leukemiaan assosioitunut proteiini

https://www.ncbi.nlm.nih.gov/gene/9920

Official Symbol

KBTBD11

Official Full Name

kelch repeat and BTB domain containing 11

Also known as

KLHDC7C

Expression

Broad expression in brain (RPKM 16.2), kidney (RPKM 8.3) and 19 other tissues See more

Orthologs

Preferred Names

kelch repeat and BTB domain-containing protein 11

Names

chronic myelogenous leukemia-associated protein

kelch domain-containing protein 7B

kelch repeat and BTB (POZ) domain containing 11

 623 a.a.

1. NM_014867.3 → NP_055682.1  kelch repeat and BTB domain-containing protein 11
   See identical proteins and their annotated locations for NP_055682.1
   
   

   ORIGIN      
           1 mehavapcvl ypgtepgaag esesegaasp aqtpcslgas lcfssgeesp pqslasaaeg
          61 aatsppssgg prvverqwea gsagaaspee laspeeracp eepaapspep rvwledpasp
         121 eepgepapvp pgfgavygep dlvlevsgrr lrahkavlaa rsdyfraras rdvlrvqgvs
         181 ltalrlllad aysgrmagvr pdnvaevvag arrlqlpgaa qratdavgpq lslancyevl
         241 saakrqrlne lrdaaycfms dhylevlrep avfgrlsgae rdlllrrrlr agrahllaaa
         301 lgpagerags rpqspsgdad argdaavycf haaagewrel trlpegapar gcglcvlyny
         361 lfvaggvapa gpdgrarpsd qvfcynpatd swsavrplrq arsqlrllal dghlyavgge
         421 cllsverydp radrwapvap lprgafavah eattchgeiy vsggslfyrl lkydprrdew
         481 qecpcsssre rsadmvaldg fiyrfdlsgs rgeaqaagps gvsvsryhcl akqwspcvap
         541 lrlpggptgl qpfrcaaldg aiycvsragt wrfqparege aggdagqggg fealgapldv
         601 rgvlipfals lpekpprgeq gap

   Conserved Domains (6) summary

   smart00612
   Location:413 → 449

   Kelch; Kelch domain

   smart00225
   Location:141 → 226

   BTB; Broad-Complex, Tramtrack and Bric a brac

   sd00038
   Location:350 → 398

   Kelch; KELCH repeat [structural motif]

   pfam00651
   Location:141 → 225

   BTB; BTB/POZ domain

   pfam01344
   Location:348 → 399

   Kelch_1; Kelch motif

   pfam05334
   Location:54 → 136

   DUF719; Protein of unknown function (DUF719)This family consists of several eukaryotic proteins of unknown function.

Related articles in PubMed

1. A polymorphic MYC response element in KBTBD11 influences colorectal cancer risk, especially in interaction with an MYC-regulated SNP rs6983267. Gong J, et al. Ann Oncol, 2018 Mar 1. PMID 29267898
2. High-resolution mapping and transcript identification at the progressive epilepsy with mental retardation locus on chromosome 8p. Ranta S, et al. Genome Res, 1997 Sep. PMID 9314494
3. Slowed conduction and thin myelination of peripheral nerves associated with mutant rho Guanine-nucleotide exchange factor 10. Verhoeven K, et al. Am J Hum Genet, 2003 Oct. PMID 14508709, Free PMC Article
4. Genome-wide association study of selenium concentrations. Cornelis MC, et al. Hum Mol Genet, 2015 Mar 1. PMID 25343990, Free PMC Article
5. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. Nagase T, et al. DNA Res, 1998 Oct 30. PMID 9872452

See all (7) citations in PubMed

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GeneRIFs: Gene References Into Functions

What's a GeneRIF? Our study highlighted the high colorectal cancer risk of people carrying MYC rs6983267 G and KBTBD11 rs11777210 C alleles

 LISÄTIETOA 10.11. 2019 Kelch-motiivista

 https://www.ncbi.nlm.nih.gov/pubmed/30837587

 

Sci Rep. 2019 Mar 5;9(1):3523. doi: 10.1038/s41598-019-40240-2.

KBTBD11, a novel BTB-Kelch protein, is a negative regulator of osteoclastogenesis through controlling Cullin3-mediated ubiquitination of NFATc1.

Narahara S^1,2, Sakai E¹, Kadowaki T³, Yamaguchi Y¹, Narahara H¹, Okamoto K^1,4, Asahina I², Tsukuba T⁵.

Author information

Abstract Kelch repeat and BTB domain-containing protein 11 (KBTBD11) is a member of the KBTBD subfamily of proteins that possess a BTB domain and Kelch repeats. Despite the presence of the Kbtbd11 gene in mammalian genomes, there are few reports about KBTBD11 at present. In this study, we identified the novel protein KBTBD11 as a negative regulator of osteoclast differentiation. We found that expression of  NFAT Small-interfering-RNA-mediated knockdown of KBTBD11 enhanced osteoclast formation, and markedly increased the expression of several osteoclast marker genes compared with control cells. Conversely, KBTBD11 overexpression impaired osteoclast differentiation, and decreased the expression of osteoclast marker genes. Among six major signaling pathways regulating osteoclast differentiation, KBTBD11 predominantly influenced the nuclear factor of activated T cell cytoplasmic-1 (NFATc1) pathway. Mechanistically, KBTBD11 was found to interact with an E3 ubiquitin ligase, Cullin3. Further experiments involving immunoprecipitation and treatment with MG132, a proteasome inhibitor, showed that the KBTBD11-Cullin3 promotes ubiquitination and degradation of NFATc1 by the proteasome. Considering that NFATc1 is an essential factor for osteoclast differentiation, the KBTBD11 and Cullin3 probably regulate the levels of NFATc1 through the ubiquitin-proteasome degradation system. Thus, KBTBD11 negatively modulates osteoclast differentiation by controlling Cullin3-mediated ubiquitination of NFATc1.

DOI:

10.1038/s41598-019-40240-2

NFAT1c  tekee interaktion Pim-1 kanssa:
 https://en.wikipedia.org/wiki/PIM1

 

1. (PDF) Understanding the functional discrepancy of Pim-1 in ...
   
   https://www.academia.edu/24324323/Understanding...
   
   Gene CARDS  NAMES: KBTBD11

   • Kelch Repeat And BTB Domain Containing 11 ^{2 3 5}
   • Kelch Repeat And BTB Domain-Containing Protein 11 ^{3 4}
   • Chronic Myelogenous Leukemia-Associated Protein ^{3 4}
   • Kelch Repeat And BTB (POZ) Domain Containing 11 ^{2 3}
   • Kelch Domain-Containing Protein 7B ^{3 4}
   • KLHDC7C ^{3 4}
   • KIAA0711 ⁴
   • CMLAP ⁴

KLHDC7B (22q13.33) (Koko: 1235 aa peptidi( Polyglutamiinijaksoja, runsas proliinipitoisuus , atrofiini-1 domeeni

https://www.ncbi.nlm.nih.gov/gene/113730  ( Tämä Kelch-proteiini  voi  vaikuttaa  CREB:iin ,  transkriptionaalisen koaktivaattoriin  sitoutuvan   CBP:n   (creb binding protein) pois vatäytymisstä tumasta atrofiini-1  domeenin kautta ja se taas aiheuttaa että glukoneogeneesi  voi päästä alkamaan. Luulisi että  tuumorissa sellainen olisi edullista  syövän  energia-aineenvaihdunnalle.  Neuronedegeneratiivisissa taudeissa POLYGLUTAMIINITAUDEISSA, on tätä mekanimsia atrofiini-1 domeenista.

Preferred Names

kelch domain-containing protein 7B

1. NM_138433.5 → NP_612442.3  kelch domain-containing protein 7B

2. ORIGIN      
           1 miqgtlepdg plwgwdwdsd ndwdsavlal lalavvaata lalhwfgsgh dqeaaepvst
          61 algaqphqag gaelalqpks kvsdgsegqs pgqgkpeppg rgqqspvpaa apggglaama
         121 rlplktavee arrealgqqr gsatpaapra egkepprpgt allgrseagg msapllihft
         181 prspgseaea etggvrassr qaagpagqqd tgpwqagagp sgsmgrgrgr rrrmdagsgd
         241 rarrprkldp lrlgaagsvw davdgaaald aharglptgp plaqepalpa lpapralqpg
         301 sqtegsgakg gwsreasgvp apgggwpwvs revpgtrsfg papdstrpwl esppqgrpls
         361 sqgpgatgay dageagadss rdnspaadlg ptrppeqakp aaaghsraps rsreprprsa
         421 sppaapgpgf ppealtlpsp sdflplevtq dpsvgenlra apapssasaq vltsapasvl
         481 apalasspss aptsattsts sptsapapap tsaptstpap apspaaaatp apapvpvptl
         541 tppspaltpv ptpalspapt paltpaaspa ltpvptpals paptpaptpa aspapaptsa
         601 ptptpaaspa padgskpqes valprryqeg qvsaswgnli amvlrshpfp rqdrpqgsvp
         661 ravpgspvgp ststhsedrh gpsssvgtvi gtgtgglvea ggqpqprsse tngspspdpp
         721 pglrgegtre ksldplpqaa mprgpaqppa qrppgpaass sarrsqpvpq lrkrsrceia
         781 psseqevrpa asgdpqgeap geggspagrs galtekqeea rklmvflqrp ggwgvvegpr
         841 kpssralepa taaalrrrld lgscldvlaf aqqhgepgla qetyalmsdn llrvlgdpcl
         901 yrrlsaadre rilslrtgrg ravlgvlvlp slyqggrsgl prgprgeepp aaapvslplp
         961 ahlhvfnpre ntwrpltqvp eeaplrgcgl ctmhnylfla ggirgsgaka vcsnevfcyn
        1021 pltniwsqvr pmqqaraqlk lvaldgllya iggeclysme cydprtdawt praplpagtf
        1081 pvaheavacr gdiyvtgghl fyrllryspv kdawdecpys ashrrssdiv alggflyrfd
        1141 llrgvgaavm ryntvtgsws raaslplpap aplhcttlgn tiyclnpqvt atftvsggta
        1201 qfqakelqpf plgstgvlsp filtlppedr lqtsl
   //

   
   
   

   Conserved Domains (3) summary

   sd00038
   Location:986 → 1032

   Kelch; KELCH repeat [structural motif]

   cl26464
   Location:52 → 421

   Atrophin-1; Atrophin-1 family
   

   Atrophin-1 family

   Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteristic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

   cl28614
   Location:966 → 1138

   BTB; Broad-Complex, Tramtrack and Bric a brac

KLHDC7A (1p36.13) ( Koko :777 aa)

https://www.ncbi.nlm.nih.gov/gene/127707
 https://www.ncbi.nlm.nih.gov/protein/NP_689588.2

Preferred Names

kelch domain-containing protein 7A

1. NM_152375.2 → NP_689588.2  kelch domain-containing protein 7A
   See identical proteins and their annotated locations for NP_689588.2
   

   ORIGIN      
           1 mfprgaeaqd whldmqltgk vvlsaaalll vtvayrlyks rpapaqrwgg ngqaeakeea
          61 egsgqpavqe aspgvllrgp rrrrsskrae apqgcscenp rgpyvlvtga tstdrkpqrk
         121 gsgeerggqg sdseqvppcc psqetrtavg snpdpphfpr lgsepksspa gliaaadgsc
         181 aggepspwqd skprehpglg qlepphchyv aplqgssdmn qswvftrvig vsreeagale
         241 aasdvdltlh qqegapnssy tfssiarvrm eehfiqkaeg veprlkgkvy dyyvestsqa
         301 ifqgrlaprt aaltevpspr pppgslgtga asggqagdtk gaaeraaspq tgpwpstrgf
         361 srkesllqia enpelqlqpd gfrlpappcp dpgalpglgr ssrephvqpv agtnffhipl
         421 tpasapqvrl dlgncyevlt lakrqnleal keaaykvmse nylqvlrspd iygclsgaer
         481 elilqrrlrg rqylvvadvc pkedsgglcc yddeqdvwrp larmppeavs rgcaicslfn
         541 ylfvvsgcqg pghqpssrvf cynpltgiws evcplnqarp hcrlvaldgh lyaiggecln
         601 sverydprld rwdfapplps dtfalahtat vrakeifvtg gslrfllfrf saqeqrwwag
         661 ptggskdrta emvavngfly rfdlnrslgi avyrcsastr lwyecatyrt pypdafqcav
         721 vdnliycvgr rstlcflads vsprfvpkel rsfpapqgtl lptvltlptp dlpqtrv

   Conserved Domains (4) summary

   smart00612
   Location:542 → 589

   Kelch; Kelch domain

   sd00038
   Location:531 → 575

   Kelch; KELCH repeat [structural motif]

   pfam01344
   Location:578 → 619

   Kelch_1; Kelch motif

   cl06652
   Location:430 → 470

   BACK_like; BTB-And-C-terminal-Kelch (BACK) domain and similar domains

1. Association between LEKR1-CCNL1 and IGSF21-KLHDC7A gene polymorphisms and diabetic retinopathy of type 2 diabetes mellitus in the Chinese Han population. Lin X, et al. J Gene Med, 2016 Oct. PMID 27607899
2. Genome-wide meta-analysis for severe diabetic retinopathy. Grassi MA, et al. Hum Mol Genet, 2011 Jun 15. PMID 21441570, Free PMC Article
3. Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Rose JE, et al. Mol Med, 2010 Jul-Aug. PMID 20379614, Free PMC Article
4. Complete sequencing and characterization of 21,243 full-length human cDNAs. Ota T, et al. Nat Genet, 2004 Jan. PMID 14702039
5. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Strausberg RL, et al. Proc Natl Acad Sci U S A, 2002 Dec 24. PMID 12477932, Free PMC Article

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. Results suggest that LEKR1-CCNL1 and IGSF21-KLHDC7A gene polymorphisms influence the development of diabetic retinopathy (DR).
2. Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator)

KBTBD10 = KLHL41(2q31.1), Sarcosin

https://www.ncbi.nlm.nih.gov/gene/?term=KBTBD10

KBTBD9 = KLHL29( 2p24.1)

https://www.ncbi.nlm.nih.gov/gene/?term=Homo+sapiens+KBTBD9

FBXL17, (5q21.3), BTB-dimerisaatioitten kontrollantti, CLR1 adaptori, F-box motiivi, SCF- kompleksi (SKP1, CUL1, F-boxproteiinit)

https://www.ncbi.nlm.nih.gov/pubmed/30190310/

Official Symbol

FBXL17

Official Full Name

F-box and leucine rich repeat protein 17 p

Also known as

Fbl17; Fbx13; FBXO13

Summary

Members of the F-box protein family, such as FBXL17, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

Expression

Ubiquitous expression in thyroid (RPKM 4.5), brain (RPKM 4.2) and 25 other tissues See more

Ref.

'Science. 2018 Oct 12;362(6411). pii: eaap8236. doi: 10.1126/science.aap8236. Epub 2018 Sep 6.

Dimerization quality control ensures neuronal development and survival.

. Abstract

Aberrant complex formation by recurrent interaction modules, such as BTB domains, leucine zippers, or coiled coils, can disrupt signal transduction, yet whether cells detect and eliminate complexes of irregular composition is unknown. By searching for regulators of the BTB family, we discovered a quality control pathway that ensures functional dimerization [dimerization quality control (DQC)]. Key to this network is the E3 ligase SCF^FBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation. Underscoring the physiological importance of DQC, SCF^FBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells. We conclude that metazoan organisms actively monitor BTB dimerization, and we predict that distinct E3 ligases similarly control complex formation by other recurrent domains.

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

KBTBD8, (3p14.1), TA-KR, TAKRP , T-soluaktivaation kelch toistoja omaava proteiini

KBTBD8
https://www.ncbi.nlm.nih.gov/gene/84541

Also known as

TAKRP; TA-KRP

Expression Broad expression in lymph node (RPKM 10.1), testis (RPKM 4.7) and 14 other tissues See more

Preferred Names

kelch repeat and BTB domain-containing protein 8

Names

T-cell activation kelch repeat protein

kelch repeat and BTB (POZ) domain containing 8

1. NM_032505.3 → NP_115894.2  kelch repeat and BTB domain-containing protein 8
   See identical proteins and their annotated locations for NP_115894.2
2.  

   ORIGIN      
           1 maasadlsks sptpngipss dpasdamdpf hacsilkqlk tmydegqltd ivvevdhgkt
          61 fschrnvlaa ispyfrsmft sgltestqke vrivgveaes mdlvlnyayt srvilteanv
         121 qalftaasif qipsiqdqca kymishldpq nsigvfifad hyghqelgdr skeyirkkfl
         181 cvtkeqeflq ltkdqlisil dsddlnvdre ehvyesiirw feheqnerev hlpeifakci
         241 rfplmedtfi ekippqfaqa iakscvekgp sntngctqrl gmtasemiic fdaahkhsgk
         301 kqtvpcldiv tgrvfklckp pndlrevgil vspdndiyia ggyrpsssev sidhkaendf
         361 wmydhstnrw lskpsllrar igcklvyccg kmyaiggrvy egdgrnslks vecydsrenc
         421 wttvcampva mefhnaveyk ekiyvlqgef flfyepqkdy wgfltpmtvp riqglaavyk
         481 dsiyyiagtc gnhqrmftve aydielnkwt rkkdfpcdqs inpylklvlf qnklhlfvra
         541 tqvtveehvf rtsrknslyq yddiadqwmk vyetpdrlwd lgrhfecava klypqclqkv
         601 l
   //

   
   

   REFERENCE   1  (residues 1 to 601)
     AUTHORS   Werner A, Baur R, Teerikorpi N, Kaya DU and Rape M.
     TITLE     Multisite dependency of an E3 ligase controls
               monoubiquitylation-dependent cell fate decisions
     JOURNAL   Elife 7, e35407 (2018)
      PUBMED   29999490
     REMARK    GeneRIF: The authors found that CUL3 complexed with KBTBD8
               monoubiquitylates its essential targets only after these have been
               phosphorylated in multiple motifs by CK2, a kinase whose levels
               gradually increase during embryogenesis.
               Publication Status: Online-Only 

   Metazoan development depends on tightly regulated gene expression 
   programs that instruct progenitor cells to adopt specialized fates. 
   Recent work found that posttranslational modifications, such as 
   monoubiquitylation, can determine cell fate also independently of 
   effects on transcription, yet how monoubiquitylation is implemented 
   during development is poorly understood. Here, we have identified a 
   regulatory circuit that controls monoubiquitylation-dependent neural 
   crest specification by the E3 ligase CUL3 and its substrate adaptor 
   KBTBD8. We found that CUL3KBTBD8 monoubiquitylates its 
   essential targets only after these have been phosphorylated in multiple 
   motifs by CK2, a kinase whose levels gradually increase during 
   embryogenesis. Its dependency on multisite phosphorylation allows CUL3KBTBD8
    to convert the slow rise in embryonic CK2 into decisive recognition of 
   ubiquitylation substrates, which in turn is essential for neural crest 
   specification. We conclude that multisite dependency of an E3 ligase 
   provides a powerful mechanism for switch-like cell fate transitions 
   controlled by monoubiquitylation.

   Conserved Domains (6) summary

   smart00612
   Location:337 → 388

   Kelch; Kelch domain

   PHA03098
   Location:50 → 516

   PHA03098; kelch-like protein; Provisional

   sd00038
   Location:330 → 376

   Kelch; KELCH repeat [structural motif]

   pfam00651
   Location:39 → 144

   BTB; BTB/POZ domain

   pfam01344
   Location:379 → 428

   Kelch_1; Kelch motif

   pfam07707
   Location:153 → 250

   BACK; BTB And C-terminal Kelch

Related articles in PubMed

1. Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions. Werner A, et al. Elife, 2018 Jul 12. PMID 29999490, Free PMC Article
2. Dimerization quality control ensures neuronal development and survival. Mena EL, et al. Science, 2018 Oct 12. PMID 30190310
3. Cell-fate determination by ubiquitin-dependent regulation of translation. Werner A, et al. Nature, 2015 Sep 24. PMID 26399832, Free PMC Article
4. Identification of 15 loci influencing height in a Korean population. Kim JJ, et al. J Hum Genet, 2010 Jan. PMID 19893584
5. Deep sequencing and proteomic analysis of the microRNA-induced silencing complex in human red blood cells. Azzouzi I, et al. Exp Hematol, 2015 May. PMID 25681748

See all (14) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

TIAM 1(21q22.11) Rac-1 spedifinen GEF (guanosiininukleotidien vaihtotekijä)

 TIAM1
https://www.ncbi.nlm.nih.gov/gene/7074 

Also known as

TIAM-1

Summary

This gene encodes a RAC1-specific guanine nucleotide exchange factor (GEF). GEFs mediate the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). The binding of GTP induces a conformational change in RAC1 that allows downstream effectors to bind and transduce a signal. This gene thus regulates RAC1 signaling pathways that affect cell shape, migration, adhesion, growth, survival, and polarity, as well as influencing actin cytoskeletal formation, endocytosis, and membrane trafficking. This gene thus plays an important role in cell invasion, metastasis, and carcinogenesis.

 In addition to RAC1, the encoded protein activates additional Rho-like GTPases such as CDC42, RAC2, RAC3 and RHOA.  

This gene encodes multiple protein isoforms that experience a diverse array of intramolecular, protein-protein, and phosphorylation interactions as well as phosphoinositide (PI)  binding. Both the longer and shorter isoforms have C-terminal Dbl homology (DH) and pleckstrin homology (PH) domains while only the longer isoforms of this gene have the N-terminal myristoylation site and the downstream N-terminal PH domain, ras-binding domain (RBD), and PSD-95/DlgA/ZO-1 (PDZ) domain. [provided by RefSeq, Jul 2017]

Expression

Broad expression in esophagus (RPKM 7.7), skin (RPKM 6.8) and 23 other tissues See more

Orthologs

mouse all

Preferred Names

T-lymphoma invasion and metastasis-inducing protein 1

Names

T cell lymphoma invasion and metastasis 1

human T-lymphoma invasion and metastasis inducing TIAM1 protein

https://www.sciencedirect.com/science/article/abs/pii/S0898656813002532
Metformiini ja TIAM-1

Related articles in PubMed

1. Competition between TIAM1 and Membranes Balances Endophilin A3 Activity in Cancer Metastasis. Poudel KR, et al. Dev Cell, 2018 Jun 18. PMID 29920278, Free PMC Article
2. Upregulation of Tiam1 contributes to cervical cancer disease progression and indicates poor survival outcome. Yang Y, et al. Hum Pathol, 2018 May. PMID 29452216
3. The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain. Xu Z, et al. J Biol Chem, 2017 Oct 27. PMID 28882897, Free PMC Article
4. Expression of T-lymphoma invasion and metastasis factor on the occurrence of oral squamous cell carcinoma. Song B, et al. J Biol Regul Homeost Agents, 2017 Apr-Jun. PMID 28685528
5. TIAM1 variants improve clinical outcome in neuroblastoma. Sanmartín E, et al. Oncotarget, 2017 Jul 11. PMID 28423360, Free PMC Article

See all (157) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. our study demonstrated that upregulation of Tiam1 contributes to cervical cancer disease progression and indicates poor survival outcome
2. Overexpression of miR-10b in HeLa and SiHa suppressed cell proliferation, migration and invasion, and induced apoptosis and miR-10b downregulation had opposite effects. Mechanistically, T-cell lymphoma invasion and metastasis 1 (Tiam1) was identified as a direct and functional target of miR-10b.
3. Study in hepatocellular carcinoma (HCC) cells proves that SETDB1 promotes the proliferation and migration of cells by forming SETDB1-Tiam1 compounds. SETDB1-Tiam1 compounds were involved in a novel pathway, which regulated epigenetic modification of gene expression in HCC patients samples.
4. Down-regulating Tiam1 expression resulted in the down-regulation of circRNA-ACAP2 expression and up-regulation of miR-21-5P expression.
5. The effects of Tiam1 on metastasis and EMT mediated by the Wnt/beta-catenin pathway were reversed by Rac1 silencing, suggesting that the prometastatic effect of Tiam1 is mediated by the activation of Rac1. These results indicate that Tiam1 may be a prognostic factor and potential therapeutic target for the treatment of thyroid cancers.
6. These findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis.
7. Competing interactions of EndoA3 with membrane versus TIAM1 modulate hyperproliferative and metastatic phenotypes. Disruption of EndoA3-membrane interactions stimulates TIAM1 and small GTPases in vitro, and further promotes pro-metastatic phenotypes in vivo.
8. PDZ domains direct protein-protein interactions and serve as models for protein design. This study optimized a protein design energy function for the Tiam1 and Cask PDZ domains that combines a molecular mechanics energy, Generalized Born solvent, and an empirical unfolded state model.
9. Clinical outcome was improved in tumors where a TIAM1 variant was present concomitantly with either ALK mutation or MYCN amplification.
10. the Ser179Glu mutant of SDC-4 binds strongly Tiam1, a Rac1-GEF reducing Rac1-GTP by 3-fold in MCF-7 breast adenocarcinoma cells.