4.5 Article

NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling

Journal

NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 18, Issue 12, Pages 1381-U98

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2152

Keywords

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Funding

  1. US National Institutes of Health (NIH) [P01CA102583, R01CA160457, R01CA116099, P01HD025938]
  2. National Synchrotron Light Source [BC100466]
  3. Biological and Environmental Research Department of Energy
  4. NIH National Center for Research Resources

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Members of the novel SH2-containing protein (NSP) and Crk-associated substrate (Cas) protein families form multidomain signaling platforms that mediate cell migration and invasion through a collection of distinct signaling motifs. Members of each family interact via their respective C-terminal domains, but the mechanism of this association has remained enigmatic. Here we present the crystal structures of the C-terminal domain from the NSP protein BCAR3 and the complex of NSP3 with p130Cas. BCAR3 adopts the Cdc25-homology fold of Ras GTPase exchange factors, but it has a 'closed' conformation incapable of enzymatic activity. The structure of the NSP3-p130Cas complex reveals that this closed conformation is instrumental for interaction of NSP proteins with a focal adhesion-targeting domain present in Cas proteins. This enzyme-to-adaptor conversion enables high-affinity, yet promiscuous, interactions between NSP and Cas proteins and represents an unprecedented mechanistic paradigm linking cellular signaling networks.

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