A Conserved Salt Bridge in the G Loop of Multiple Protein Kinases Is Important for Catalysis and for In Vivo Lyn Function

作者：Barouch Bentov Rina; Che Jianwei; Lee Christian C; Yang Yating; Herman Ann; Jia Yong; Velentza Anastasia; Watson James; Sternberg Luise; Kim Sunjun; Ziaee Niusha; Miller Andrew; Jackson Carie; Fujimoto Manabu; Young Mike; Batalov Serge; Liu Yi; Warmuth Markus; Wiltshire Tim; Cooke Michael P; Sauer Karsten^*

来源：Molecular Cell, 2009, 33(1): 43-52.

DOI：10.1016/j.molcel.2008.12.024

The glycine-rich G loop controls ATP binding and phosphate transfer in protein kinases. Here we show that the functions of Src family and Abl protein tyrosine kinases require an electrostatic interaction between oppositely charged amino acids within their G loops that is conserved in multiple other phylogenetically distinct protein kinases, from plants to humans. By limiting G loop. flexibility, it controls ATP binding, catalysis, and inhibition by competitive compounds such as Imatinib. In WeeB mice, mutational disruption of the interaction results in expression of a Lyn protein with reduced catalytic activity, and in perturbed B cell receptor signaling. Like Lyn(-/-) mice, WeeB mice show profound defects in B cell development and function and succumb to autoimmune glomerulonephritis. This demonstrates the physiological importance of the conserved G loop salt bridge and at the same time distinguishes the in vivo requirement for the Lyn kinase activity from other potential functions of the protein.

• 出版日期2009-1-16