title: A single residue in a novel ADP-ribosyl cyclase controls production of the calcium-mobilizing messengers cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate.
abstract: Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate are ubiquitous calcium-mobilizing messengers produced by the same family of multifunctional enzymes, the ADP-ribosyl cyclases. Not all ADP-ribosyl cyclases have been identified, and how production of different messengers is achieved is incompletely understood. Here, we report the cloning and characterization of a novel ADP-ribosyl cyclase (SpARC4) from the sea urchin, a key model organism for the study of calcium-signaling pathways. Like several other members of the ADP-ribosyl cyclase superfamily, SpARC4 is a glycoprotein targeted to the plasma membrane via a glycosylphosphatidylinositol anchor. However, unlike most other members, SpARC4 shows a remarkable preference for producing cyclic ADP-ribose over nicotinic acid adenine dinucleotide phosphate. Mutation of a single residue (tyrosine 142) within a noncanonical active site reversed this striking preference. Our data highlight further diversification of this unusual enzyme family, provide mechanistic insight into multifunctionality, and suggest that different ADP-ribosyl cyclases are fine-tuned to produce specific calcium-mobilizing messengers.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Latha
authors.initials: L
authors.lastname: Ramakrishnan
authors.forename: Hélène
authors.initials: H
authors.lastname: Muller-Steffner
authors.forename: Christophe
authors.initials: C
authors.lastname: Bosc
authors.forename: Victor D
authors.initials: VD
authors.lastname: Vacquier
authors.forename: Francis
authors.initials: F
authors.lastname: Schuber
authors.forename: Marie-Jo
authors.initials: MJ
authors.lastname: Moutin
authors.forename: Leslie
authors.initials: L
authors.lastname: Dale
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001757:Blastomeres / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D003001:Cloning, Molecular; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008845:Microinjections; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D047270:Strongylocentrotus purpuratus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology
chemical_list: D036563:Cyclic ADP-Ribose; D014443:Tyrosine; D009249:NADP; C024376:NAADP; D036541:ADP-ribosyl Cyclase
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