title: NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling.
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.
authors.affiliation: Program of Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Mace
authors.forename: Yann
authors.initials: Y
authors.lastname: Wallez
authors.forename: Małgorzata K
authors.initials: MK
authors.lastname: Dobaczewska
authors.forename: Jeongeun J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Howard
authors.initials: H
authors.lastname: Robinson
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Riedl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D017124:Conserved Sequence; D050719:Crk-Associated Substrate Protein / Q000737:chemistry* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493841:BCAR1 protein, human; C118588:BCAR3 protein, human; D050719:Crk-Associated Substrate Protein; D020662:Guanine Nucleotide Exchange Factors; C118589:SH2D3C protein, human
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