Structure/function of the soluble guanylyl cyclase catalytic domain

• Published in: Nitric oxide Vol. 77; pp. 53 - 64
• Main Authors: Childers, Kenneth C., Garcin, Elsa D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2018
• Subjects: Activation mechanism; Adenylyl cyclase; Animals; Biocatalysis; Catalytic Domain; Humans; Nitric oxide; Nitric Oxide - metabolism; Protein Conformation; S-nitrosation; Soluble guanylyl cyclase; Soluble Guanylyl Cyclase - chemistry; Soluble Guanylyl Cyclase - metabolism; Structure-Activity Relationship; S-nitrosation; GC-1; AC; Adenylyl cyclase; GCcya2; Soluble guanylyl cyclase; αβGCcat; Catalytic domain; GCCr; Activation mechanism; GCRho; Nitric oxide; S-NO
• ISSN: 1089-8603; 1089-8611
• DOI: 10.1016/j.niox.2018.04.008

Soluble guanylyl cyclase (GC-1) is the primary receptor of nitric oxide (NO) in smooth muscle cells and maintains vascular function by inducing vasorelaxation in nearby blood vessels. GC-1 converts guanosine 5′-triphosphate (GTP) into cyclic guanosine 3′,5′-monophosphate (cGMP), which acts as a second messenger to improve blood flow. While much work has been done to characterize this pathway, we lack a mechanistic understanding of how NO binding to the heme domain leads to a large increase in activity at the C-terminal catalytic domain. Recent structural evidence and activity measurements from multiple groups have revealed a low-activity cyclase domain that requires additional GC-1 domains to promote a catalytically-competent conformation. How the catalytic domain structurally transitions into the active conformation requires further characterization. This review focuses on structure/function studies of the GC-1 catalytic domain and recent advances various groups have made in understanding how catalytic activity is regulated including small molecules interactions, Cys-S-NO modifications and potential interactions with the NO-sensor domain and other proteins. •Activity of αβGCcat is low and requires other GC-1 domains for optimal activity.•αβGCcat and other cyclases share common fold and utilize base-specific residues.•S-NO in αβGCcat tunes NO sensitivity; binding to Trx and PDI can rescue activity.•Interactions between HNOX and αβGCcat hypothesized to tune GC-1 activity.•Structural transitions of αβGCcat for optimal activity remain to be determined.