| Accession: | |
|---|---|
| Functional site class: | DCAF12 C-terminal diGlu degrons |
| Functional site description: | DCAF12 degrons bind to its WD40 repeat domain through their C-terminal di-glutamate motif (Pla-Prats,2023). CCT5 is a subunit of the TRiC chaperonin carrying the C-terminal double glutamate motif. DCAF12 uses a positively charged pocket at the centre of the WD40 β‐propeller to bind the C‐terminus of CCT5. This domain:motif interaction established primarily via H-bonding and salt bridging has been characterized by cryo-electron microscopy in atomic detail (8AJM; Pla-Prats,2023). |
| ELM Description: | Two Cul4 E3 ubiquitin ligase complexes, Cul4TRPC4AP and Cul4DCAF12, have been identified as targeting C-terminal degrons (Koren,2018). The DCAF12 substrate-recognition subunit of Cullin-4 ubiquitin ligases is responsible for the recognition of the terminal di-glutamate degrons through its WD40 repeat domain (Pla-Prats,2023). Two structures were solved revealing the binding between TCPE_HUMAN(P48643) and DCA12_HUMAN (Q5T6F0). In the structure (8AJM), the binding pocket of the domain is flanked with positively charged residues, locking down Glu at the -2 position with hydrogen bonds and a double salt bridge to Arg203 and His144, while Glu at -1 can also engage these positive patches(8AJM). Inspecting (8AJO) reveals the precisely coordinated COO- via double salt bridge to Arg256. Hydrogen bonds with the pocket are also formed at -3 and -4 positions. Position -5 exits the pocket and is largely disordered (Pla-Prats,2023). Most of the well-characterized instances have C-termini natively ending in Glu-Glu, although generation of the same site through proteolysis cannot be excluded. The degron residues are rather strict: DCAF12’s WD40 repeats demand a glutamic acid at the −2 position (Timms,2020). Nevertheless, there is some flexibility in the specific residue at the C-terminal (-1) position. Although DCAF12 prefers a twin C-terminal glutamic acid (−EE) motif, other residues are also tolerated to some extent. In addition, a glutamate in the -4 position forming an H-bond with the DCAF12 backbone is also visible, raising the possibility of extending the degron motif from "EE$" to "..EE$". Several members of the melanoma antigen gene (MAGE) family, usually expressed only in the male germline but aberrantly expressed in cancers to drive tumorigenesis, have the −EE$ motif. DCAF12-mediated degradation of MAGEA3 and MAGEA6 through their C-terminal −EE$ motifs is crucial for inducing autophagy in response to nutrient deprivation (Ravichandran,2019). |
| Pattern: | ..EE$ |
| Pattern Probability: | 0.0000142 |
| Present in taxon: | Metazoa |
| Interaction Domain: |
WD40 repeat (IPR001680)
WD-40 repeats (also known as WD or beta-transducin repeats) are short ~40 amino acid motifs, often terminating in a Trp-Asp (W-D) dipeptide
(Stochiometry: 1 : 1)
|
| Acc., Gene-, Name | Start | End | Subsequence | Logic | #Ev. | Organism | Notes |
|---|---|---|---|---|---|---|---|
| P22102 GART PUR2_HUMAN |
1007 | 1010 | VASGTVQLGENGKICWVKEE | TP | 4 | Homo sapiens (Human) | |
| Q9NZB2 FAM120A F120A_HUMAN |
1115 | 1118 | TDSACRREAALEAAVLNKEE | TP | 4 | Homo sapiens (Human) | |
| Q70CQ3 USP30 UBP30_HUMAN |
514 | 517 | FYERVLSRMQHQSQECKSEE | TP | 4 | Homo sapiens (Human) | |
| P43360 MAGEA6 MAGA6_HUMAN |
311 | 314 | GGPRISYPLLHEWALREGEE | TP | 2 | Homo sapiens (Human) | |
| P43357 MAGEA3 MAGA3_HUMAN |
311 | 314 | GGPHISYPPLHEWVLREGEE | TP | 3 | Homo sapiens (Human) | |
| P48643 CCT5 TCPE_HUMAN |
538 | 541 | QMVRMILKIDDIRKPGESEE | TP | 4 | Homo sapiens (Human) |