Ubikitiiniligaasi-tyypeistä: CUL2

https://www.cell.com/cell/pdf/S0092-8674(16)30259-8.pdf

 Ensin taulukossa mainitaan  yksinkertaisemmat RING -domaanin omaavat proteiinit. Suluissa jokin esimerkki.
 Sitten on useamman alayksikön omaavat RING- E3 ubikitiiniligaasit, joihin kuuluu CUL2.
Sitten  luetellaan HECT  E3 ubikitiiniligaasit ja niistä esimerkkejä.
Viimeksi maintiaan RBR E3 ubikitiiniligasit, joissa on  RING- domaanien välissäkin RING-domaani.

1. RING E3s

RING E3s are the most abundant type of ubiquitin ligases. They are characterized by the presence of a zinc-binding domain called RING (Really Interesting New Gene)

or by a U-box domain, which adopts the same RING fold but does not contain zinc. The RING and U-box domains are responsible for binding the ubiquitin-charged E2 and

stimulating ubiquitin transfer.

RING E3s mediate a direct transfer of ubiquitin to the substrate, functioning as a scaffold to orient the ubiquitin-charged E2 with respect to the substrate protein. 
RING E3s can function as

•  monomers, (c-CBL)
•  homodimers, (CIAP, RNF4, BIRC7, IDOL, TRIM5alfa,...)
• heterodimers,  (BRCA1-BARD1, Mdm2-MdmX, RING1B-Bmc1

Homodimeric RINGs can normally bind two E2s (one per each monomer); this does not appear to be the case for heterodimeric RINGs

Similarly, U-box domains can work as 

• monomers (E4B)
• homodimers.(CHIP, Prp19)

 2. Some RING E3s are composed by multiple subunits, 

• such as the cullin-RING ligases (CRLs). 

CRLs are a highly diverse class of ubiquitin ligases characterized by several common features. They are assembled on a cullin scaffold (CUL1;  CUL2) , binding a RING-box (Rbx)  protein at its N terminus and an adaptor protein (Skp1)  and a substrate receptor (responsible for substrate specificity) at its C terminus ( F-box protein, Skp2)

Another important multi subunit E3 is the anaphase-promoting complex/cyclosome (APC/C).

3. HECT-like  ubiquitine ligases 

• NEDD4  (Smurf1;  2 ww motifs, Smurf2, 3 wwmotifs, Itch 3, wwp1, 4 ww motifs) 
• HERC ( small HERCs, large HERCs)
• other HECT ub.ligases (E6Ap) 

4. RBR,  E3 ubiquitine ligases, (RING between  two RINGs) 
Parkin
Parc
RNF144(A/B)
HOIP, HHARI

•  
• Lisäys: löysin maininnan ubikitiiniligaasista.  Koetan selvittää sen ryhmän. Ovat RNF-ryhmää. Niitä on niin paljon, että pitää ottaa yksi kerrallaan   esiin ja katsoa mikä niiden toiminta-alue on. 
•  https://www.ncbi.nlm.nih.gov/pubmed/12670940
  

  Abstract

  Apolipoprotein B100 (apoB) is a large (520-kDa) complex secretory protein; its secretion is regulated posttranscriptionally by several degradation pathways. The best described of these degradative processes is co-translational ubiquitinylation and proteasomal degradation of nascent apoB, involving the 70- and 90-kDa heat shock proteins and the multiple components of the proteasomal pathway.
  Ubiquitinylation involves several proteins, including ligases called E3s, that coordinate the covalent binding of ubiquitin to target proteins. The recent discovery that tumor autocrine motility factor receptor, also known as gp78, is an endoplasmic reticulum (ER)-associated E3, raised the possibility that this E3 might be involved in the ER-associated degradation of nascent apoB. In a series of experiments in HepG2 cells, we demonstrated that overexpression of gp78 was sufficient for increased ubiquitinylation and proteasomal degradation of apoB, with reduced secretion of apoB-lipoproteins. This action of gp78 was specific: overexpression of the protein did not affect secretion of either albumin or apolipoprotein AI. Furthermore, overexpression of a cytosolic E3, Itch, had no effect on apoB secretion. Finally, using an in vitro translation system, we demonstrated that gp78 led to increased ubiquitinylation and proteasomal degradation of apoB48. Together, these results indicate that an ER-associated protein, gp78, is a bona fide E3 ligase in the apoB ER-associated degradation pathway.
  
  https://www.ncbi.nlm.nih.gov/pubmed/29374057
  Abstract
  
  

  J Biol Chem. 2018 Mar 16;293(11):4047-4055. doi: 10.1074/jbc.RA117.001260. Epub 2018 Jan 26. Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase. Jiang LY¹, Jiang W¹, Tian N¹, Xiong YN¹, Liu J¹, Wei J¹, Wu KY¹, Luo J¹, Shi XJ², Song BL³.

  Abstract

  Cholesterol biosynthesis is tightly regulated in the cell. For example, high sterol concentrations can stimulate degradation of the rate-limiting cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCR). HMGCR is broken down by the endoplasmic reticulum membrane-associated (ERAD) protein complexes consisting of insulin-induced genes (Insigs) and the E3 ubiquitin ligase gp78. Here we found that HMGCR degradation is partially blunted in Chinese hamster ovary (CHO) cells lacking gp78 (gp78-KO). To identify other ubiquitin ligase(s) that may function together with gp78 in triggering HMGCR degradation, we performed a small-scale short hairpin RNA-based screening targeting endoplasmic reticulum-localized E3s. We found that knockdown of both ring finger protein 145 (Rnf145) and gp78 genes abrogates sterol-induced degradation of HMGCR in CHO cells. We also observed that RNF145 interacts with Insig-1 and -2 proteins and ubiquitinates HMGCR. Moreover, the tetrapeptide sequence YLYF in the sterol-sensing domain and the Cys-537 residue in the RING finger domain were essential for RNF145 binding to Insigs and RNF145 E3 activity, respectively. Of note, amino acid substitutions in the YLYF or of Cys-537 completely abolished RNF145-mediated HMGCR degradation. In summary, our study reveals that RNF145, along with gp78, promotes HMGCR degradation in response to elevated sterol levels and identifies residues essential for RNF145 function.

  KEYWORDS:

  ER-associated degradation; HMG-CoA reductase; Insig; RNF145; cholesterol metabolism; gp78; lipid; ubiquitin ligase; ubiquitylation (ubiquitination)