Kataniinin merkityksestä aivojen muodostumiselle: struktuuri, dendriittipuusto

https://www.sciencedirect.com/science/article/pii/S0896627314010952

Summary

Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.

p60/KATNA1 is a member of the AAA (ATPases Associated with diverse cellular Activities) domain containing protein family, whereas p80/KATNB1 binds to p60 and targets it to subcellular structures including the centrosome, further mediating its interactions with Dynein, LIS1, and NDEL1 (Hartman et al., 1998, McNally et al., 2000).
A missense mutation in the highly conserved WD40 domain of Katnb1 has been shown to cause azoospermia and male sterility in mice (O’Donnell et al., 2012).

KATNA1 (6q25.1)https://www.ncbi.nlm.nih.gov/gene/11104

Summary

Microtubules, polymers of alpha and beta tubulin subunits, form the mitotic spindle of a dividing cell and help to organize membranous organelles during interphase. Katanin is a heterodimer that consists of a 60 kDa ATPase (p60 subunit A 1) and an 80 kDa accessory protein (p80 subunit B 1). The p60 subunit acts to sever and disassemble microtubules, while the p80 subunit targets the enzyme to the centrosome. This protein is a member of the AAA family of ATPases. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Feb 2011]

Expression

Broad expression in testis (RPKM 18.8), ovary (RPKM 7.2) and 24 other tissues See more

Preferred Names

katanin p60 ATPase-containing subunit A1

Names

katanin p60 (ATPase containing) subunit A 1

katanin p60 subunit A1

p60 katanin

1. NM_007044.4 → NP_008975.1  katanin p60 ATPase-containing subunit A1 isoform 1
   See identical proteins and their annotated locations for NP_008975.1
   
   Status: REVIEWED

   Description

   Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).

   Conserved Domains (3) summary

   smart00382
   Location:241 → 382

   AAA; ATPases associated with a variety of cellular activities

   pfam00004
   Location:245 → 381

   AAA; ATPase family associated with various cellular activities (AAA)

   pfam09336
   Location:456 → 489

   Vps4_C; Vps4 C terminal oligomerization domain

 KATNB1  (16q21) https://www.ncbi.nlm.nih.gov/gene/10300

Also known as

KAT; LIS6

Summary

Microtubules, polymers of alpha and beta tubulin subunits, form the mitotic spindle of a dividing cell and help to organize membranous organelles during interphase. Katanin is a heterodimer that consists of a 60 kDa ATPase (p60 subunit A 1) and an 80 kDa accessory protein (p80 subunit B 1). The p60 subunit acts to sever and disassemble microtubules, while the p80 subunit targets the enzyme to the centrosome. Katanin is a member of the AAA family of ATPases. [provided by RefSeq, Jul 2008]

Expression

Broad expression in testis (RPKM 14.6), brain (RPKM 7.5) and 24 other tissues See more

Preferred Names

katanin p80 WD40 repeat-containing subunit B1

Names

katanin (80 kDa)

katanin p80 (WD repeat containing) subunit B 1

katanin p80 (WD40-containing) subunit B 1

katanin p80 WD40-containing subunit B1

katanin p80 subunit B1

p80 katanin

1. NM_005886.3 → NP_005877.2  katanin p80 WD40 repeat-containing subunit B1
   See identical proteins and their annotated locations for NP_005877.2
   
   
   

   ORIGIN      
           1 matpvvtkta wklqeivaha snvsslvlgk asgrllatgg ddcrvnlwsi nkpncimslt
          61 ghtspvesvr lntpeeliva gsqsgsirvw dleaakilrt lmghkanics ldfhpygefv
         121 asgsqdtnik lwdirrkgcv fryrghsqav rclrfspdgk wlasaaddht vklwdltagk
         181 mmsefpghtg pvnvvefhpn eyllasgssd rtirfwdlek fqvvsciege pgpvrsvlfn
         241 pdgcclysgc qdslrvygwe percfdvvlv nwgkvadlai cndqligvaf sqsnvssyvv
         301 dltrvtrtgt vardpvqdhr plaqplpnps aplrriyerp sttcskpqrv kqnseserrs
         361 psseddrder esraeiqnae dyneifqpkn sisrtpprrs epfpappedd aatakeaakp
         421 spamdvqfpv pnlevlprpp vvastpapka epaiipatrn epiglkasdf lpavkipqqa
         481 elvdedamsq irkghdtmcv vltsrhknld tvravwtmgd iktsvdsava indlsvvvdl
         541 lnivnqkasl wkldlcttvl pqiekllqsk yesyvqtgct slklilqrfl plitdmlaap
         601 psvgvdisre erlhkcrlcy kqlksisglv ksksglsgrh gstfrelhll masld

   Conserved Domains (4) summary

   cd00200
   Location:7 → 257

   WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from  its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

   sd00039
   Location:67 → 103

   7WD40; WD40 repeat [structural motif]
   

   WD40 repeats in seven bladed beta propellers

   The WD40 repeat is found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing, and cytoskeleton assembly. It typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40. Between the GH and WD dipeptides lies a conserved core. It forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel beta-sheet. The WD40 sequence repeat originally described in literature forms the first three strands of one blade and the last strand in the next blade. The C-terminal WD40 repeat completes the blade structure of the N-terminal WD40 repeat to create the closed ring propeller-structure. The residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands, allowing them to bind either stably or reversibly.

   pfam13925
   Location:497 → 648

   Katanin_con80; con80 domain of Katanin

   cl26386
   Location:386 → 494

   DNA_pol3_gamma3; DNA polymerase III subunits gamma and tau domain
    III
   
   
   

   Region          285..434
                        /region_name="Interaction with PAFAH1B1. {ECO:0000250}"
                        /experiment="experimental evidence, no additional details
                        recorded"
                        /note="propagated from UniProtKB/Swiss-Prot (Q9BVA0.1)"
        Region          <386 ..="">494
                        /region_name="DNA_pol3_gamma3"
                        /note="DNA polymerase III subunits gamma and tau domain
                        III; cl26386"
                        /db_xref="CDD:331207"
        Site            395
                        /site_type="phosphorylation"
                        /experiment="experimental evidence, no additional details
                        recorded"
                        /note="Phosphothreonine. {ECO:0000244|PubMed:23186163};
                        propagated from UniProtKB/Swiss-Prot (Q9BVA0.1)"
        Region          433..655
                        /region_name="Interaction with KATNA1 and NDEL1.
                        {ECO:0000250}"
                        /experiment="experimental evidence, no additional details
                        recorded"
                        /note="propagated from UniProtKB/Swiss-Prot (Q9BVA0.1)"
        Region          497..648
                        /region_name="Katanin_con80"
                        /note="con80 domain of Katanin; pfam13925"
                        /db_xref="CDD:316447"