NSP-Cas Protein Structures Reveal a Promiscuous Interaction Module in Cell Signaling

Nat Struct Mol Biol. 2011 Nov 13;18(12):1381-7. doi: 10.1038/nsmb.2152.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites
  • Conserved Sequence
  • Crk-Associated Substrate Protein / chemistry*
  • Crk-Associated Substrate Protein / metabolism
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Models, Molecular
  • Protein Structure, Tertiary
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • BCAR1 protein, human
  • BCAR3 protein, human
  • Crk-Associated Substrate Protein
  • Guanine Nucleotide Exchange Factors
  • SH2D3C protein, human

Associated data

  • PDB/3T6A
  • PDB/3T6G