Program of Apoptosis and Cell Death Research, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
Nat Struct Mol Biol. 2011 Nov 13;18(12):1381-7. 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.
新型 SH2 结构域包含蛋白（NSP）和 Crk 相关底物（Cas）蛋白家族成员形成多结构域信号平台，通过一系列不同的信号基序介导细胞迁移和侵袭。每个家族的成员通过其各自的 C 端结构域相互作用，但这种关联的机制仍然是个谜。本文呈现了 NSP 蛋白 BCAR3 的 C 端结构域以及 NSP3 与 p130Cas 复合物的晶体结构。BCAR3 采用 Ras GTP 酶交换因子的 Cdc25 同源折叠，但具有“封闭”构象，无法进行酶活性。NSP3-p130Cas 复合物的结构揭示了这种封闭构象对于 NSP 蛋白与 Cas 蛋白中存在的粘着斑靶向结构域相互作用至关重要。这种酶到衔接子的转换使 NSP 和 Cas 蛋白之间能够发生高亲和力但又混杂的相互作用，并代表了一种前所未有的将细胞信号网络联系起来的机制范例。
