title: Hrs-2 is an ATPase implicated in calcium-regulated secretion.
abstract: Associations between proteins present on neurotransmitter-containing vesicles and on the presynaptic membrane are thought to underlie docking and fusion of synaptic vesicles with the plasma membrane, which are obligate steps in regulated neurotransmission. SNAP-25 resides on the plasma membrane and interacts with syntaxin (a plasma membrane t-SNARE) and VAMP (a vesicle v-SNARE) to form a core protein complex thought to be an intermediate in a biochemical pathway that is essential for vesicular transport. We have now characterized a protein, Hrs-2, that interacts with SNAP-25. The binding of Hrs-2 to SNAP-25 is inhibited by calcium in the physiological concentration range that supports synaptic transmission. Furthermore, Hrs-2 binds and hydrolyses nucleoside triphosphates with kinetics that suggest that ATP is the physiological substrate for this enzyme. Hrs-2 is expressed throughout the brain and is present in nerve terminals. Moreover, recombinant Hrs-2 inhibits calcium-triggered 3H-noradrenaline release from permeabilized PC12 cells. Our results suggest a role for Hrs-2 in regulating secretory processes through calcium- and nucleotide-dependent modulation of vesicle-trafficking protein complexes.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine, California 94305, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bean
authors.forename: R
authors.initials: R
authors.lastname: Seifert
authors.forename: Y A
authors.initials: YA
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Sacks
authors.forename: R H
authors.initials: RH
authors.lastname: Scheller
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D005089:Exocytosis; D006801:Humans; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D009708:Nucleotidases / Q000378:metabolism; D016716:PC12 Cells; D010750:Phosphoproteins; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25; D016335:Zinc Fingers
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; C494208:SNAP25 protein, human; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D009708:Nucleotidases; D000251:Adenosine Triphosphatases; C115505:Hgs protein, rat; D002118:Calcium; D009638:Norepinephrine