Per-ARNT-Sim Domains in Nitric Oxide Signaling by Soluble Guanylyl Cyclase

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3 Scopus citations

Abstract

Nitric oxide (NO) regulates large swaths of animal physiology including wound healing, vasodilation, memory formation, odor detection, sexual function, and response to infectious disease. The primary NO receptor is soluble guanyly/guanylate cyclase (sGC), a dimeric protein of ∼150 kDa that detects NO through a ferrous heme, leading to a large change in conformation and enhanced production of cGMP from GTP. In humans, loss of sGC function contributes to multiple disease states, including cardiovascular disease and cancer, and is the target of a new class of drugs, sGC stimulators, now in clinical use. sGC evolved through the fusion of four ancient domains, a heme nitric oxide / oxygen (H-NOX) domain, a Per-ARNT-Sim (PAS) domain, a coiled coil, and a cyclase domain, with catalysis occurring at the interface of the two cyclase domains. In animals, the predominant dimer is the α1β1 heterodimer, with the α1 subunit formed through gene duplication of the β1 subunit. The PAS domain provides an extensive dimer interface that remains unchanged during sGC activation, acting as a core anchor. A large cleft formed at the PAS-PAS dimer interface tightly binds the N-terminal end of the coiled coil, keeping this region intact and unchanged while the rest of the coiled coil repacks, and the other domains reposition. This interface buries ∼3000 Å2 of monomer surface and includes highly conserved apolar and hydrogen bonding residues. Herein, we discuss the evolutionary history of sGC, describe the role of PAS domains in sGC function, and explore the regulatory factors affecting sGC function.

Original languageEnglish (US)
Article number168235
JournalJournal of Molecular Biology
Volume436
Issue number3
DOIs
StatePublished - Feb 1 2024

Keywords

  • PAS domain
  • cGMP
  • coiled coil
  • conformational change
  • heme

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Molecular Biology

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