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From Proteopedia
The structure of the Fem1B:FNIP1 complex
Structural highlights
FunctionFEM1B_MOUSE Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (By similarity). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (By similarity). The CRL2(FEM1B) complex specifically recognizes proteins ending with -Gly-Leu-Asp-Arg, such as CDK5R1, leading to their ubiquitination and degradation (By similarity). Also acts as a regulator of the reductive stress response by mediating ubiquitination of reduced FNIP1: in response to reductive stress, the CRL2(FEM1B) complex specifically recognizes a conserved Cys degron in FNIP1 when this degron is reduced, leading to FNIP1 degradation and subsequent activation of mitochondria to recalibrate reactive oxygen species (ROS) (PubMed:32941802). Promotes ubiquitination of GLI1, suppressing GLI1 transcriptional activator activity (By similarity). Promotes ubiquitination and degradation of ANKRD37 (PubMed:21723927). Promotes ubiquitination and degradation of SLBP (By similarity). Involved in apoptosis by acting as a death receptor-associated protein that mediates apoptosis (By similarity). Also involved in glucose homeostasis in pancreatic islet (PubMed:16024793). May also act as an adapter/mediator in replication stress-induced signaling that leads to the activation of CHEK1 (By similarity).[UniProtKB:Q9UK73][1] [2] [3] Publication Abstract from PubMedAlthough oxidative phosphorylation is best known for producing ATP, it also yields reactive oxygen species (ROS) as invariant byproducts. Depletion of ROS below their physiological levels, a phenomenon known as reductive stress, impedes cellular signaling and has been linked to cancer, diabetes, and cardiomyopathy. Cells alleviate reductive stress by ubiquitylating and degrading the mitochondrial gatekeeper FNIP1, yet it is unknown how the responsible E3 ligase CUL2(FEM1B) can bind its target based on redox state and how this is adjusted to changing cellular environments. Here, we show that CUL2(FEM1B) relies on zinc as a molecular glue to selectively recruit reduced FNIP1 during reductive stress. FNIP1 ubiquitylation is gated by pseudosubstrate inhibitors of the BEX family, which prevent premature FNIP1 degradation to protect cells from unwarranted ROS accumulation. FEM1B gain-of-function mutation and BEX deletion elicit similar developmental syndromes, showing that the zinc-dependent reductive stress response must be tightly regulated to maintain cellular and organismal homeostasis. Structural basis and regulation of the reductive stress response.,Manford AG, Mena EL, Shih KY, Gee CL, McMinimy R, Martinez-Gonzalez B, Sherriff R, Lew B, Zoltek M, Rodriguez-Perez F, Woldesenbet M, Kuriyan J, Rape M Cell. 2021 Oct 14;184(21):5375-5390.e16. doi: 10.1016/j.cell.2021.09.002. Epub , 2021 Sep 24. PMID:34562363[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Large Structures | Mus musculus | Gee CL | Manford AG | Mena EL | Rape M
