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Dimerization Region of Soluble Guanylate Cyclase Characterized by Bimolecular Fluorescence Complementation in Vivo

Cardiovascular Research, Bayer HealthCare, Wuppertal, Germany (C.R., D.-J.A., L.S.H., J.P.S.); Martin-Luther-University, School of Pharmacy, Halle, Germany (C.R., L.S.H., H.S., J.P.S.); Department of Pharmacology, Monash University, Melbourne, Clayton, Victoria, Australia (P.M.S., H.H.H.W.S.); Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (H.S.); and Helios Klinikum, Institute for Pathology, Wuppertal, Germany (D.-J.A.)

The ubiquitously expressed nitric oxide (NO) receptor soluble guanylate cyclase (sGC) plays a key role in signal transduction. Binding of NO to the N-terminal prosthetic heme moiety of sGC results in 200-fold activation of the enzyme and an increased conversion of GTP into the second messenger cGMP. sGC exists as a heterodimer the dimerization of which is mediated mainly by the central region of the enzyme. In the present work, we constructed deletion mutants within the predicted dimerization region of the sGC ₁- and ₁-subunit to precisely map the sequence segments crucial for subunit dimerization. To track mutation-induced alterations of sGC dimerization, we used a bimolecular fluorescence complementation approach that allows visualizing sGC heterodimerization in a noninvasive manner in living cells. Our study suggests that segments spanning amino acids ₁363–372, ₁403–422, ₁440–459, ₁212–222, ₁304–333, ₁344–363, and ₁381–400 within the predicted dimerization region are involved in the process of heterodimerization and therefore in the expression of functional sGC.

Address correspondence to: Priv.-Doz. Dr. Johannes-Peter Stasch, Bayer HealthCare, Cardiovascular Research, Aprather Weg 18a, D-42096 Wuppertal, Germany. E-mail: johannes-peter.stasch{at}bayerhealthcare.com

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