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8ttq

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Cryo-EM structure of the inner MKLN1 dimer from an autoinhibited MKLN1 tetramer

Structural highlights

8ttq is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.27Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MKLN1_HUMAN Component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (PubMed:29911972). Required for internalization of the GABA receptor GABRA1 from the cell membrane via endosomes and subsequent GABRA1 degradation (By similarity). Acts as a mediator of cell spreading and cytoskeletal responses to the extracellular matrix component THBS1 (PubMed:18710924).[UniProtKB:O89050]^[1] ^[2]

Publication Abstract from PubMed

A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development.

FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation.,Barbulescu P, Chana CK, Wong MK, Ben Makhlouf I, Bruce JP, Feng Y, Keszei AFA, Wong C, Mohamad-Ramshan R, McGary LC, Kashem MA, Ceccarelli DF, Orlicky S, Fang Y, Kuang H, Mazhab-Jafari M, Pezo RC, Bhagwat AS, Pugh TJ, Gingras AC, Sicheri F, Martin A Nat Commun. 2024 Aug 30;15(1):7541. doi: 10.1038/s41467-024-52009-x. PMID:39215025^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Valiyaveettil M, Bentley AA, Gursahaney P, Hussien R, Chakravarti R, Kureishy N, Prag S, Adams JC. Novel role of the muskelin-RanBP9 complex as a nucleocytoplasmic mediator of cell morphology regulation. J Cell Biol. 2008 Aug 25;182(4):727-39. PMID:18710924 doi:10.1083/jcb.200801133
↑ Lampert F, Stafa D, Goga A, Soste MV, Gilberto S, Olieric N, Picotti P, Stoffel M, Peter M. The multi-subunit GID/CTLH E3 ubiquitin ligase promotes cell proliferation and targets the transcription factor Hbp1 for degradation. Elife. 2018 Jun 18;7:e35528. PMID:29911972 doi:10.7554/eLife.35528
↑ Barbulescu P, Chana CK, Wong MK, Ben Makhlouf I, Bruce JP, Feng Y, Keszei AFA, Wong C, Mohamad-Ramshan R, McGary LC, Kashem MA, Ceccarelli DF, Orlicky S, Fang Y, Kuang H, Mazhab-Jafari M, Pezo RC, Bhagwat AS, Pugh TJ, Gingras AC, Sicheri F, Martin A. FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation. Nat Commun. 2024 Aug 30;15(1):7541. PMID:39215025 doi:10.1038/s41467-024-52009-x