A Conserved Salt Bridge in the G‐Loop of Src Family Protein Tyrosine Kinases is Essential for Lyn Function in Mice

Abstract

The glycine‐rich G‐loop is important for ATP binding and phosphate transfer in protein kinases. Here we show that the function of Src family protein tyrosine kinase G‐loops requires an electrostatic interaction between a conserved N‐terminal basic and a conserved C‐terminal acidic amino acid. By limiting G‐loop flexibility, this salt bridge is required for high affinity ATP binding and catalysis. In WeeB mice, mutation of the conserved acidic amino acid results in expression of a mutant Lyn protein with strongly reduced catalytic activity. This leads to moderate perturbation of B cell receptor signaling, which is strongly impaired in Lyn−/− mice. Surprisingly, WeeB mice still show profound defects in B cell development and function and succumb to autoimmune glomerulonephritis, key aspects of the Lyn−/− phenotype. This demonstrates the physiological importance of the conserved G‐loop salt bridge and in addition unveils an extraordinary sensitivity of B cell function to the Lyn kinase activity.