Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism

• DOI: 10.7554/elife.86784.3
• Publication Date: 2023-08-03T15:40:42Z
• Authors: Nathanael A Caveney; Naotaka Tsutsumi; K Christopher Garcia
• Keywords: GUCY2D; CDC37; Chaperone (clinical)

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