Structure of a regulatory complex involving the Abl SH3 domain, the Crk SH2 domain, and a Crk-derived phosphopeptide

被引:61
作者
Donaldson, LW
Gish, G
Pawson, T
Kay, LE
Forman-Kay, JD [1 ]
机构
[1] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada
[2] Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada
[3] Univ Toronto, Dept Chem, Toronto, ON M5S 1A8, Canada
[4] York Univ, Dept Biol, N York, ON M3J 1P3, Canada
[5] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Program Mol Biol & Canc, Toronto, ON M5G 1X5, Canada
[6] Hosp Sick Children, Struct Biol & Biochem Program, Toronto, ON M5G 1X8, Canada
关键词
NMR; signal transduction; domain orientation; modular binding domain;
D O I
10.1073/pnas.212518799
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
on phosphorylation of Y221 by Abelson (Abl) kinase, the Crk-II adapter protein undergoes an intramolecular reorganization initiated by the binding of its own Src homology 2 (SH2) domain to the pY221 site. Conformational changes induced by phosphotyrosine recognition promote the binding of the Src homology 3 (SH3) domain of the AN tyrosine kinase to a proline-rich loop located between the betaD and betaE strands of the SH2 domain (DE loop). We have determined the NMR solution structure of the ternary complex of the Abl SH3 domain with the Crk SH2 domain bound to a Crk pY221 phosphopepticle. The SH2 domain bridges two ligands that bind at distinct sites. The interaction between the AN SH3 domain and the Crk SH2 domain is localized to a canonical eight-residue site within the DE loop. From N-15 relaxation experiments, the DE loop of the SH2 domain in the complex displays a significant degree of conformational freedom. The structural and dynamic data therefore indicate that these SH2 and SH3 domains do not assume a unique orientation with respect to one another; rather, they appear to be only tethered via the DE loop. Thus, SH2 domain-SH3 domain interactions do not require additional tertiary contacts or restriction of domain orientation when a recognition motif is presented in a mobile loop. This complex between the Abl SH3 domain, Crk SH2 domain, and Crk phosphopepticle is an example of the extremely modular nature of regulatory proteins that provides a rich repertoire of mechanisms for control of biological function.
引用
收藏
页码:14053 / 14058
页数:6
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