A function-structure model for NGF-activated TRK

Mechanisms regulating transit of receptor tyrosine kinases (RTKs) from inac tive to active states are incompletely described, but require autophosphory lation of tyrosine(s) within a kinase domain 'activation loop'. Here, we em ploy functional biological assays with mutated TRK receptors to assess a 's witch' model for RTK activation. In this model: (i) ligand binding stimulat es activation loop tyrosine phosphorylation; (ii) these phosphotyrosines fo rm specific charge pairs with nearby basic residues; and (iii) the charge p airs stabilize a functionally active conformation in which the activation l oop is restrained from blocking access to the kinase catalytic core. Our fi ndings both support this model and identify residues that form specific cha rge pairs with each of the three TRK activation loop phosphotyrosines.