01808nas a2200133 4500008004100000245006200041210006200103260000800165300000900173520136400182100002101546700002001567856008701587 2021 eng d00aGPCRs that Rh oar the Guanine nucleotide exchange factors0 aGPCRs that Rh oar the Guanine nucleotide exchange factors cAPR a1-163 a

Cell migration, a crucial step in numerous biological processes, is tightly regulated in space and time. Cells employ Rho GTPases, primarily Rho, Rac, and Cdc42, to regulate their motility. Like other small G proteins, Rho GTPases function as biomolecular switches in regulating cell migration by operating between GDP bound 'OFF' and GTP bound 'ON' states. Guanine nucleotide exchange factors (GEFs) catalyse the shuttling of GTPases from OFF to ON state. G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors that are involved in many signalling phenomena including cell survival and cell migration events. In this review, we summarize signalling mechanisms, involving GPCRs, leading to the activation of RhoGEFs. GPCRs exhibit diverse GEF activation modes that include the interaction of heterotrimeric G protein subunits with different domains of GEFs, phosphorylation, protein-protein interaction, protein-lipid interaction, and/or a combination of these processes.

1 aOmble, Aishwarya1 aKulkarni, Kiran uhttp://library.ncl.res.in/content/gpcrs-rh-oar-guanine-nucleotide-exchange-factors02255nas a2200169 4500008004100000245010000041210006900141260000900210300000800219490000600227520165300233100002101886700002201907700002001929700002001949856011601969 2024 eng d00aDishevelled2 activates WGEF via its interaction with a unique internal peptide motif of the GEF0 aDishevelled2 activates WGEF via its interaction with a unique in cMAY  a5430 v73 a

The Wnt-planar cell polarity (Wnt-PCP) pathway is crucial in establishing cell polarity during development and tissue homoeostasis. This pathway is found to be dysregulated in many pathological conditions, including cancer and autoimmune disorders. The central event in Wnt-PCP pathway is the activation of Weak-similarity guanine nucleotide exchange factor (WGEF) by the adapter protein Dishevelled (Dvl). The PDZ domain of Dishevelled2 (Dvl2PDZ) binds and activates WGEF by releasing it from its autoinhibitory state. However, the actual Dvl2PDZ binding site of WGEF and the consequent activation mechanism of the GEF have remained elusive. Using biochemical and molecular dynamics studies, we show that a unique ``internal-PDZ binding motif'' (IPM) of WGEF mediates the WGEF-Dvl2PDZ interaction to activate the GEF. The residues at P 2 , P 0 , P -2 and P -3 positions of IPM play an important role in stabilizing the WGEFpep-Dvl2PDZ interaction. Furthermore, MD simulations of modelled Dvl2PDZ-WGEFIPM peptide complexes suggest that WGEF-Dvl2PDZ interaction may differ from the reported Dvl2PDZ-IPM interactions. Additionally, the apo structure of human Dvl2PDZ shows conformational dynamics different from its IPM peptide bound state, suggesting an induced fit mechanism for the Dvl2PDZ-peptide interaction. The current study provides a model for Dvl2 induced activation of WGEF. This study identifies a unique ``internal-PDZ binding motif'' (IPM) of WGEF that mediates its interaction with Dvl2PDZ, leading to the release of GEF from its autoinhibitory state. It further unravels the underlying mutual Dvl2-IPM recognition aspects.

1 aOmble, Aishwarya1 aMahajan, Shrutika1 aBhoite, Ashwini1 aKulkarni, Kiran uhttp://library.ncl.res.in/content/dishevelled2-activates-wgef-its-interaction-unique-internal-peptide-motif-gef