9nr3
From Proteopedia
CRBN-DDB1 in complex with GLUL-cN
Structural highlights
DiseaseGLNA_HUMAN Defects in GLUL are the cause of congenital systemic glutamine deficiency (CSGD) [MIM:610015. CSGD is a rare developmental disorder with severe brain malformation resulting in multi-organ failure and neonatal death. Glutamine is largely absent from affected patients serum, urine and cerebrospinal fluid.[1] FunctionGLNA_HUMAN This enzyme has 2 functions: it catalyzes the production of glutamine and 4-aminobutanoate (gamma-aminobutyric acid, GABA), the latter in a pyridoxal phosphate-independent manner (By similarity). Essential for proliferation of fetal skin fibroblasts.[2] Publication Abstract from PubMedThe E3 ligase substrate adapter cereblon (CRBN), the primary target of clinical agents thalidomide and lenalidomide, recognizes endogenous substrates bearing the C-terminal cyclic imide modification. Although C-terminal cyclic imides can form spontaneously, an enzyme that regulates their formation and thereby promotes a biological pathway connecting substrates to CRBN is unknown. Here we report that protein carboxymethyltransferase (PCMT1) promotes formation of C-terminal cyclic imides on C-terminal asparagine residues of CRBN substrates. PCMT1 and CRBN coregulate the levels of metabolic enzymes including glutamine synthetase and inorganic pyrophosphatase 1 in vitro, in cells and in vivo, and this regulation is associated with the proepileptic phenotype of CRBN knockout mouse models. The discovery of an enzyme that regulates CRBN substrates through the C-terminal cyclic imide reveals a previously unknown biological pathway that is perturbed by thalidomide derivatives and provides a biochemical basis for the connection between multiple biological processes and CRBN. PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates.,Zhao Z, Xu W, Feng EY, Cao S, Hermoso-Lopez A, Pena-Vega P, Lloyd HC, Porter AKD, Guzman M, Zheng N, Woo CM Nat Chem Biol. 2025 Dec 29. doi: 10.1038/s41589-025-02106-9. PMID:41461925[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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