Comprehensive Domain Insertion Profiling to Study Inward Rectifier K+ Channel Folding Robustness

Abstract

Inward Rectifier K+ (KIR) channels play key roles in the operation of cells in neuromuscular and other tissue. Pathogenic variants are linked to numerous neurological, cardiovascular, and metabolic disorders. Although some variants cause gating defects in KIR by altering ligand regulation or ion permeation, there is growing evidence that many -perhaps most- variants cause defects in folding and trafficking of KIR. Despite the central role for folding and trafficking in the disease etiology, there have been to date no comprehensive large-scale studies that determine sequence and structural determinants of folding and trafficking robustness in KIR.