Identification of Amino Acid Residues Involved in the pH Sensitivity of Receptor Tyrosine Kinase IRR

IRR is a member of the insulin receptor (IR) family that has no known endogenous peptide agonists but can be activated by weak alkaline environments and has thus been proposed to function as an extracellular pH sensor. IRR activation by alkali is determined by its N-terminal extracellular region. Using recently published Cryo-EM structure of IRR ectodomain we identify three amino acids (R87, K143 and S516) that may be involved in the IRR activation by alkali. In this report we show that the triple substitution of these amino acids with alanine leads to complete disappearance of the IRR pH sensitivity. Thus, these amino acids can form one of the possible pH sensor sites in the IRR molecule.