8uy3
Fem1B with FNIP1 and Tom20 fragment
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, PubMed:34562363). Mechanistically, recognizes and binds reduced FNIP1 through two interface zinc ions, which act as a molecular glue that recruit reduced FNIP1 to FEM1B (PubMed:34562363). 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] [4] Publication Abstract from PubMedWhile reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2(FEM1B)), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2(FEM1B) substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival. Reactive oxygen species control protein degradation at the mitochondrial import gate.,McMinimy R, Manford AG, Gee CL, Chandrasekhar S, Mousa GA, Chuang J, Phu L, Shih KY, Rose CM, Kuriyan J, Bingol B, Rape M Mol Cell. 2024 Dec 5;84(23):4612-4628.e13. doi: 10.1016/j.molcel.2024.11.004. PMID:39642856[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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