Novel Disease Variants Reveal Critical Functions for Intrinsically Disordered Regions Encoded by the Diabetes Gene CLEC16A

Abstract

The diabetes gene CLEC16A encodes an E3 ubiquitin ligase, which maintains glucose homeostasis and pancreatic ß-cell insulin secretion via the mitochondrial quality control pathway. Despite the importance of CLEC16A to ß-cell health, its structural and functional domains are unknown. Recent genetic studies identify a CLEC16A variant with increased disease susceptibility that favors an alternatively spliced isoform lacking both C-terminal and internal regions of the protein. Predictive algorithms, circular dichroism spectroscopy, and carbon-detect NMR approaches suggest the CLEC16A internal and C-terminal disease-associated domains lie within intrinsically disordered protein regions (IDPRs).