9upz

Structural highlights

Function

KCMF1_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme and then transfers it to targeted substrates, promoting their degradation by the proteasome (PubMed:15581609, PubMed:25582440, PubMed:34893540, PubMed:37891180, PubMed:38297121). Together with UBR4, component of the N-end rule pathway: ubiquitinates proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their degradation (PubMed:34893540, PubMed:37891180). Does not ubiquitinate proteins that are acetylated at the N-terminus (PubMed:37891180). Together with UBR4, part of a protein quality control pathway that catalyzes ubiquitination and degradation of proteins that have been oxidized in response to reactive oxygen species (ROS): recognizes proteins with an Arg-CysO3(H) degron at the N-terminus, and mediates assembly of heterotypic 'Lys-63'-/'Lys-27'-linked branched ubiquitin chains on oxidized proteins, leading to their degradation by autophagy (PubMed:34893540). Catalytic component of the SIFI complex, a multiprotein complex required to inhibit the mitochondrial stress response after a specific stress event has been resolved: ubiquitinates and degrades (1) components of the HRI-mediated signaling of the integrated stress response, such as DELE1 and EIF2AK1/HRI, as well as (2) unimported mitochondrial precursors (PubMed:38297121). Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1 (PubMed:38297121).^{[1] [2] [3] [4] [5]}

References

1. ↑ Jang JH. FIGC, a novel FGF-induced ubiquitin-protein ligase in gastric cancers. FEBS Lett. 2004 Dec 3;578(1-2):21-5. PMID:15581609 doi:10.1016/j.febslet.2004.10.071
2. ↑ Hong JH, Kaustov L, Coyaud E, Srikumar T, Wan J, Arrowsmith C, Raught B. KCMF1 (potassium channel modulatory factor 1) Links RAD6 to UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4) and lysosome-mediated degradation. Mol Cell Proteomics. 2015 Mar;14(3):674-85. PMID:25582440 doi:10.1074/mcp.M114.042168
3. ↑ Heo AJ, Kim SB, Ji CH, Han D, Lee SJ, Lee SH, Lee MJ, Lee JS, Ciechanover A, Kim BY, Kwon YT. The N-terminal cysteine is a dual sensor of oxygen and oxidative stress. Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2107993118. PMID:34893540 doi:10.1073/pnas.2107993118
4. ↑ Varland S, Silva RD, Kjosås I, Faustino A, Bogaert A, Billmann M, Boukhatmi H, Kellen B, Costanzo M, Drazic A, Osberg C, Chan K, Zhang X, Tong AHY, Andreazza S, Lee JJ, Nedyalkova L, Ušaj M, Whitworth AJ, Andrews BJ, Moffat J, Myers CL, Gevaert K, Boone C, Martinho RG, Arnesen T. N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity. Nat Commun. 2023 Oct 27;14(1):6774. PMID:37891180 doi:10.1038/s41467-023-42342-y
5. ↑ Haakonsen DL, Heider M, Ingersoll AJ, Vodehnal K, Witus SR, Uenaka T, Wernig M, Rapé M. Stress response silencing by an E3 ligase mutated in neurodegeneration. Nature. 2024 Feb;626(8000):874-880. PMID:38297121 doi:10.1038/s41586-023-06985-7