7csp
Structure of Ephexin4 IDPSHStructure of Ephexin4 IDPSH
Structural highlights
FunctionARHGG_MOUSE Guanyl-nucleotide exchange factor of the RHOG GTPase stimulating the exchange of RHOG-associated GDP for GTP. May play a role in chemotactic cell migration by mediating the activation of RAC1 by EPHA2. May also activate CDC42 (By similarity). Publication Abstract from PubMedEphexin family guanine nucleotide exchange factors (GEFs) transfer signals from Eph tyrosine kinase receptors to Rho GTPases, which play critical roles in diverse cellular processes, as well as cancers and brain disorders. Here, we elucidate the molecular basis underlying inhibition and activation of Ephexin family RhoGEFs. The crystal structures of partially and fully autoinhibited Ephexin4 reveal that the complete autoinhibition requires both N- and C-terminal inhibitory modes, which can operate independently to impede Ras homolog family member G (RhoG) access. This double inhibition mechanism is commonly employed by other Ephexins and SGEF, another RhoGEF for RhoG. Structural, enzymatic, and cell biological analyses show that phosphorylation of a conserved tyrosine residue in its N-terminal inhibitory domain and association of PDZ proteins with its C-terminal PDZ-binding motif may respectively relieve the two autoinhibitory modes in Ephexin4. Our study provides a mechanistic framework for understanding the fine-tuning regulation of Ephexin4 GEF activity and offers possible clues for its pathological dysfunction. Double inhibition and activation mechanisms of Ephexin family RhoGEFs.,Zhang M, Lin L, Wang C, Zhu J Proc Natl Acad Sci U S A. 2021 Feb 23;118(8). pii: 2024465118. doi:, 10.1073/pnas.2024465118. PMID:33597305[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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