title: The Neuronal Migration Factor srGAP2 Achieves Specificity in Ligand Binding through a Two-Component Molecular Mechanism.
abstract: srGAP proteins regulate cell migration and morphogenesis by shaping the structure and dynamics of the cytoskeleton and membranes. First discovered as intracellular effectors for the Robo1 axon-guidance receptor, srGAPs were later identified as interacting with several other nuclear and cytoplasmic proteins. In all these cases, the srGAP SH3 domain mediates protein-protein interactions by recognizing a short proline-rich segment on the cognate-binding partner. However, as interactions between the isolated SH3 domain and a selected set of ligands show weak affinity and low specificity, it is not clear how srGAPs are precisely recruited to their signaling sites. Here, we report a two-component molecular mechanism that regulates ligand binding to srGAP2 by on the one hand dramatically tightening their association and on the other, moderately autoinhibiting and restricting binding. Our results allow the design of point mutations for better probing of srGAP2 activities, and may facilitate the identification of new srGAP2 ligands.
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Guez-Haddad
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Sporny
authors.affiliation: Biolojic Design Ltd., Ramat Gan 5290002, Israel.
authors.forename: Yehezkel
authors.initials: Y
authors.lastname: Sasson
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel.
authors.forename: Lada
authors.initials: L
authors.lastname: Gevorkyan-Airapetov
authors.affiliation: Department of Organic Chemistry, Weizmann Institute of Science, 7610001 Rehovot, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Lahav-Mankovski
authors.affiliation: Department of Organic Chemistry, Weizmann Institute of Science, 7610001 Rehovot, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Margulies
authors.affiliation: Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, 38042 Grenoble, France.
authors.forename: Jens
authors.initials: J
authors.lastname: Radzimanowski
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel. Electronic address: yarden.opatowsky@biu.ac.il.
authors.forename: Yarden
authors.initials: Y
authors.lastname: Opatowsky
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D055232:Proline-Rich Protein Domains; D011485:Protein Binding; D013379:Substrate Specificity; D018909:src Homology Domains
chemical_list: D020690:GTPase-Activating Proteins; D008024:Ligands; C501995:SRGAP2 protein, human