The Neuronal Migration Factor srGAP2 Achieves Specificity in Ligand Binding through a Two-Component Molecular Mechanism

Julia Guez-Haddad, Michael Sporny, Yehezkel Sasson, Lada Gevorkyan-Airapetov, Naama Lahav-Mankovski, David Margulies, Jens Radzimanowski, Yarden Opatowsky

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Summary 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.

Original languageEnglish
Pages (from-to)1989-2000
Number of pages12
Issue number11
StatePublished - 22 Mar 2015

Bibliographical note

Funding Information:
This paper is dedicated to the memory of the late Dr. Felix Frolow, a pioneer of cryocrystallography. The authors thank Alexander Varvak, Ilana Lebenthal, Eitan Lerner, Sivan Shemesh, and Sharon Victor of Bar-Ilan University. Thanks are extended to the staff of beamlines BM29, ID23, and ID29 of ESRF, and the staff of BESSY II BL14.1. This work was supported by funds from the ISF (grant no. 182/10, to Y.O.) and BSF (grant no. 2013310, to Y.O.).

Publisher Copyright:
© 2015 Elsevier Ltd All rights reserved.


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