While the role of the phosphorylation state on mGC activity has been explored in relative detail, how the heat shock protein 90 (Hsp90) is able to regulate mGC activity is largely unknown. In addition, the PK domains of mGCs are regulated through phosphorylation ( Potter and Garbers, 1992 Potter and Hunter, 1998 Vaandrager et al., 1993) and via association with heat shock proteins (Hsp) ( Kumar et al., 2001). The PK domain is largely thought to be involved in scaffolding and physical transduction of the extracellular rearrangements to the GC domain, in some respects similar to the role of the PK domain in the Janus kinases of the cytokine signaling system ( Glassman et al., 2022). These membrane receptor GCs consist of an extracellular ligand binding domain (ECD), which acts as a conformational switch to drive intracellular rearrangements to activate the receptor ( He et al., 2001) a transmembrane region (TM) a kinase homology domain or pseudokinase domain (PK) a dimerization domain and a GC domain, which acts to produce cGMP. Meanwhile, GC-C is the target of clinically approved laxative agonists, linaclotide, and plecanatide ( Miner, 2020 Yu and Rao, 2014), which increase intestinal fluid secretion. In the case of NPR-A and B, their role in regulating blood pressure in response to natriuretic peptide hormones (ANP, BNP, and CNP) has led to the exploration of agonists for use in the treatment of cardiac failure ( Kobayashi et al., 2012).
Of note are the membrane receptor guanylyl cyclases (mGC) GC-A and GC-B, also known as natriuretic peptide receptors A and B (NPR-A and NPR-B), respectively, and GC-C, all of which have been a focus of therapeutic development. Largely, cGMP is produced in response to the activation of guanylyl cyclases (GC), a class of receptors that contains both heteromeric soluble receptors (α 1, α 2, β 1, and β 2 in humans) and five homomeric membrane receptors (GC-A, GC-B, GC-C, GC-E, and GC-F in humans). eLife assessmentĬyclic guanosine monophosphate (cGMP) is an important second messenger for signaling in mammalian physiology, with roles in platelet aggregation, neurotransmission, sexual arousal, gut peristalsis, bone growth, intestinal fluid secretion, lipolysis, phototransduction, cardiac hypertrophy, oocyte maturation, and blood pressure regulation ( Potter, 2011). Given the known druggability of Hsp90, these insights can guide the further development of membrane receptor guanylyl cyclase-targeted therapeutics and lead to new avenues to treat hypertension, inflammatory bowel disease, and other membrane receptor guanylyl cyclase-related conditions. Furthermore, this work shows how membrane receptor guanylyl cyclases hijack the regulatory mechanisms used for active kinases to facilitate their regulation. As a membrane protein and non-kinase client of Hsp90–Cdc37, this work shows the remarkable plasticity of Cdc37 to interact with a broad array of clients with significant sequence variation. We present the 3.9 Å resolution cryo-EM 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. The structural mechanisms which influence these important physiological processes have yet to be explored. Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, from regulating blood pressure to intestinal fluid secretion.
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