Higher susceptibility to heme oxidation and lower protein stability of the rare α1C517Yβ1 sGC variant associated with moyamoya syndrome

摘要: Abstract NO sensitive soluble guanylyl cyclase (sGC) plays a key role in mediating physiological functions of NO. Genetic alterations the GUCY1A3 gene, coding for α1 subunit sGC, are associated with several cardiovascular dysfunctions. A rare sGC variant Cys517 → Tyr substitution α1subunit, has been moyamoya disease and achalasia. In this report we characterize properties variant. Purified α1C517Yβ1 preserved only ~25% its cGMP-forming activity showed an elevated Km GTP substrate. However, mutant enzyme retained high affinity robust activation by NO, similar to wild type sGC. was more specific heme oxidizers less responsive reducing agents. When expressed COS7 cells, much stronger response cinaciguat or gemfibrozil, which targets apo-sGC ferric heme, as compared relative also observed purified absence αCys517β stable than under normal conditions exhibited accelerated degradation upon induction cellular oxidative stress. We conclude that diminished is aggravated susceptibility stress protein stability. The combination these deficiencies contributes severity achalasia symptoms human carriers