Reviewer #3 (Public Review): Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism

Abstract

Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, ranging from regulation of blood pressure to the regulation of intestinal fluid secretion. The structural mechanisms which influence the regulation of these important physiological effects have yet to be explored. We present the 3.9 Å resolution cryoEM structure of the human membrane receptor guanylyl cyclase GC-C in complex with Hsp90 and its co-chaperone Cdc37, providing insight into the mechanism of Cdc37 mediated binding of GC-C to the Hsp90 regulatory complex. As a membrane protein and non-kinase client of Hsp90–Cdc37, this work shows remarkable plasticity of Cdc37 to interact with a broad array of clients having significant sequence variation. Further, this work shows how membrane receptor guanylyl cyclases hijack the regulatory mechanisms used for active kinases to facilitate their regulation. Given the known druggability of Hsp90, these insights can guide the further development of mGC targeted therapeutics and lead to new avenues to treat hypertension, inflammatory bowel disease, and other mGC related conditions.