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It takes two to tango: fine‐tuning of soluble guanylate cyclase activity via protein‐protein interactions and conformational changes (969.3)
Author(s) -
Garcin Elsa,
Seeger Franziska,
Quintyn Royston,
Tanimoto Akiko,
Williams Garrett,
Tsutakawa Susan,
Wysocki Vicki,
Tainer John
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.969.3
Subject(s) - chemistry , guanylate cyclase , nitric oxide , catalysis , soluble guanylyl cyclase , biophysics , receptor , microbiology and biotechnology , protein–protein interaction , biochemistry , biology , organic chemistry
Nitric oxide (NO) regulates many biological processes, including vasodilation, neurotransmission, and immune response. The primary receptor for NO is heterodimeric soluble guanylate cyclase (sGC), which is a validated target for therapeutic intervention in pulmonary arterial hypertension. We have solved the first x‐ray structure of wild‐type heterodimeric catalytic domains from human sGC, revealing key structural determinants for heterodimerization and conformational changes needed for catalysis. Using mass spectrometry, we determined dissociation constants for heterodimeric and homodimeric catalytic domains. Surprisingly, activity measurements showed that isolated catalytic domains are far less active than full‐length sGC. Together, our results argue that other sGC domains are crucial to promote sGC heterodimerization in vivo . We further propose an exquisite regulation mechanism whereby the catalytic activity of sGC is finely tuned by protein:protein interactions that either promote or inhibit catalytic activity. Importantly, our structural studies provide a framework to design novel sGC activators targeted at the catalytic domain. Grant Funding Source : Supported by American Heart Association