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Structural highlights

Disease

UBR4_HUMAN The gene represented in this entry may be involved in disease pathogenesis.

Function

UBR4_HUMAN E3 ubiquitin-protein ligase involved in different protein quality control pathways in the cytoplasm (PubMed:25582440, PubMed:29033132, PubMed:34893540, PubMed:37891180, PubMed:38030679, PubMed:38182926, PubMed:38297121). 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, PubMed:38030679). Recognizes both type-1 and type-2 N-degrons, containing positively charged amino acids (Arg, Lys and His) and bulky and hydrophobic amino acids, respectively (PubMed:38030679). Does not ubiquitinate proteins that are acetylated at the N-terminus (PubMed:37891180). Together with UBR5, part of a cytoplasm protein quality control pathway that prevents protein aggregation by catalyzing assembly of heterotypic 'Lys-11'-/'Lys-48'-linked branched ubiquitin chains on aggregated proteins, leading to substrate recognition by the segregase p97/VCP and degradation by the proteasome: UBR4 probably synthesizes mixed chains containing multiple linkages, while UBR5 is likely branching multiple 'Lys-48'-linked chains of substrates initially modified (PubMed:29033132). Together with KCMF1, 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). Mediates ubiquitination of ACLY, leading to its subsequent degradation (PubMed:23932781). Together with clathrin, forms meshwork structures involved in membrane morphogenesis and cytoskeletal organization (PubMed:16214886).^{[1] [2] [3] [4] [5] [6] [7] [8] [9]}

References

1. ↑ Nakatani Y, Konishi H, Vassilev A, Kurooka H, Ishiguro K, Sawada J, Ikura T, Korsmeyer SJ, Qin J, Herlitz AM. p600, a unique protein required for membrane morphogenesis and cell survival. Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15093-8. PMID:16214886 doi:10.1073/pnas.0507458102
2. ↑ Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, Xiong Y, Lei QY. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell. 2013 Aug 22;51(4):506-18. doi: 10.1016/j.molcel.2013.07.002. Epub 2013 , Aug 8. PMID:23932781 doi:http://dx.doi.org/10.1016/j.molcel.2013.07.002
3. ↑ 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
4. ↑ Yau RG, Doerner K, Castellanos ER, Haakonsen DL, Werner A, Wang N, Yang XW, Martinez-Martin N, Matsumoto ML, Dixit VM, Rape M. Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control. Cell. 2017 Nov 2;171(4):918-933.e20. PMID:29033132 doi:10.1016/j.cell.2017.09.040
5. ↑ 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
6. ↑ 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
7. ↑ Jeong DE, Lee HS, Ku B, Kim CH, Kim SJ, Shin HC. Insights into the recognition mechanism in the UBR box of UBR4 for its specific substrates. Commun Biol. 2023 Nov 29;6(1):1214. PMID:38030679 doi:10.1038/s42003-023-05602-7
8. ↑ Barnsby-Greer L, Mabbitt PD, Dery MA, Squair DR, Wood NT, Lamoliatte F, Lange SM, Virdee S. UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4. Nat Struct Mol Biol. 2024 Feb;31(2):351-363. PMID:38182926 doi:10.1038/s41594-023-01192-4
9. ↑ 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