Journal
EMBO JOURNAL
Volume 29, Issue 1, Pages 236-250Publisher
WILEY
DOI: 10.1038/emboj.2009.323
Keywords
CD44; GEF; GTPase; Par3; Rac
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- Uehara Memorial Foundation
- Foundation for NAIST
- MEXT of Japan
- Grants-in-Aid for Scientific Research [22370061, 22657031] Funding Source: KAKEN
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Tiam1 and Tiam2 (Tiam1/2) are guanine nucleotide-exchange factors that possess the PH-CC-Ex (pleckstrin homology, coiled coil and extra) region that mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. Crystal structures of the PH-CC-Ex regions revealed a single globular domain, PHCCEx domain, comprising a conventional PH subdomain associated with an antiparallel coiled coil of CC subdomain and a novel three-helical globular Ex subdomain. The PH subdomain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. Mutational and binding studies indicated that CC and Ex subdomains form a positively charged surface for protein binding. We identified two unique acidic sequence motifs in Tiam1/2-interacting proteins for binding to PHCCEx domain, Motif-I in CD44 and ephrinB's and the NMDA receptor, and Motif-II in Par3 and JIP2. Our results suggest the molecular basis by which the Tiam1/2 PHCCEx domain facilitates dual binding to membranes and signalling proteins. The EMBO Journal (2010) 29, 236-250. doi: 10.1038/emboj.2009.323; Published online 5 November 2009
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