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Blood, 13 August 2009, Vol. 114, No. 7, pp. 1396-1404. Prepublished online as a Blood First Edition Paper on June 15, 2009; DOI 10.1182/blood-2008-05-155234. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-05-155234v1 114/7/1396    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Neumüller, O. Articles by Smolenski, A. P. PubMed PubMed Citation Articles by Neumüller, O. Articles by Smolenski, A. P. Related Collections Platelets and Thrombopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS AND THROMBOPOIESIS Synaptotagmin-like protein 1 interacts with the GTPase-activating protein Rap1GAP2 and regulates dense granule secretion in platelets Olga Neumüller1, Meike Hoffmeister1, Jan Babica1, Carola Prelle1, Kristina Gegenbauer2, and Albert P. Smolenski1,2 1 Institute of Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany; and 2 Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland The small guanine-nucleotide–binding protein Rap1 plays a key role in platelet aggregation and hemostasis, and we recently identified Rap1GAP2 as the only GTPase-activating protein of Rap1 in platelets. In search of Rap1GAP2-associated proteins, we performed yeast-2-hybrid screening and found synaptotagmin-like protein 1 (Slp1) as a new binding partner. We confirmed the interaction of Rap1GAP2 and Slp1 in transfected COS-1 and HeLa cells and at endogenous level in human platelets. Mapping studies showed that Rap1GAP2 binds through amino acids T524-K525-X-T527 within its C-terminus to the C2A domain of Slp1. Slp1 contains a Rab27-binding domain, and we demonstrate that Rap1GAP2, Slp1, and Rab27 form a trimeric complex in transfected cells and in platelets. Purified Slp1 dose-dependently decreased dense granule secretion in streptolysin-O–permeabilized platelets stimulated with calcium or guanosine 5'-O-[gamma-thio] triphosphate. The isolated C2A domain of Slp1 had a stimulatory effect on granule secretion and reversed the inhibitory effect of full-length Slp1. Purified Rap1GAP2 augmented dense granule secretion of permeabilized platelets, whereas deletion of the Slp1-binding TKXT motif abolished the effect of Rap1GAP2. We conclude that Slp1 inhibits dense granule secretion in platelets and that Rap1GAP2 modulates secretion by binding to Slp1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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