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

作者：Mace Peter D; Wallez Yann; Dobaczewska Malgorzata K; Lee JeongEun J; Robinson Howard; Pasquale Elena B; Riedl Stefan J^*

来源：Nature Structural & Molecular Biology, 2011, 18(12): 1381-U98.

DOI：10.1038/nsmb.2152

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.

• 出版日期2011-12