title: Identification of a haem domain in human soluble adenylate cyclase.
abstract: The second messengers cAMP and cGMP mediate a multitude of physiological processes. In mammals, these cyclic nucleotides are formed by related Class III nucleotidyl cyclases, and both ACs (adenylate cyclases) and GCs (guanylate cyclases) comprise transmembrane receptors as well as soluble isoforms. Whereas sGC (soluble GC) has a well-characterized regulatory HD (haem domain) that acts as a receptor for the activator NO (nitric oxide), very little is known about the regulatory domains of the ubiquitous signalling enzyme sAC (soluble AC). In the present study, we identify a unique type of HD as a regulatory domain in sAC. The sAC-HD (sAC haem domain) forms a larger oligomer and binds, non-covalently, one haem cofactor per monomer. Spectral analyses and mutagenesis reveal a 6-fold co-ordinated haem iron atom, probably with non-typical axial ligands, which can bind both NO and CO (carbon monoxide). Splice variants of sAC comprising this domain are expressed in testis and skeletal muscle, and the HD displays an activating effect on the sAC catalytic core. Our results reveal a novel mechanism for regulation of cAMP signalling and suggest a need for reanalysis of previous studies on mechanisms of haem ligand effects on cyclic nucleotide signalling, particularly in testis and skeletal muscle.
authors: Department of Physiological Chemistry, Ruhr-University Bochum, Bochum, Germany.
authors: Sabine
authors: S
authors: Middelhaufe
authors: Martina
authors: M
authors: Leipelt
authors: Lonny R
authors: LR
authors: Levin
authors: Jochen
authors: J
authors: Buck
authors: Clemens
authors: C
authors: Steegborn
mesh_terms: D000262:Adenylyl Cyclases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002248:Carbon Monoxide / Q000378:metabolism; D020134:Catalytic Domain; D000242:Cyclic AMP / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013737:Testis / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D006418:Heme; D002248:Carbon Monoxide; D000242:Cyclic AMP; D007501:Iron; C579271:ADCY10 protein, human; D000262:Adenylyl Cyclases