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J Biol Chem, Vol. 274, Issue 53, 37583-37590, December 31, 1999

Human Rabaptin-5 Is Selectively Cleaved by Caspase-3 during Apoptosis^*

Eileithyia Swanton, Naomi Bishop, and Philip Woodman

From the School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom

We have previously shown that Xenopus rabaptin-5 is cleaved in apoptotic extracts, with a concomitant reduction in the ability of these extracts to support endosomal membrane fusion (Cosulich, S. C., Horiuchi, H., Zerial, M., Clarke, P. R., and Woodman, P. G. (1997) EMBO J. 16, 6182-6191). In this report we demonstrate that caspase-dependent cleavage is a conserved feature of rabaptin-5. Human rabaptin-5 is cleaved at two sites (HSLD³⁷⁹ and DESD⁴³⁸) in apoptotic HeLa extracts. Cleavage is effected by caspase-3, since it is prevented when caspase-3 activity is either inhibited by Ac-DEVD-CHO or removed by immunodepletion. Moreover, an identical pattern of cleavage is observed using recombinant caspase-3. The action of caspase-3 is highly selective; neither caspase-2 nor caspase-7 are able to cleave recombinant or cytosolic rabaptin-5. Caspase-dependent cleavage of rabaptin-5 generates two physically separated coiled coil-forming domains, the C-terminal of which retains the ability to bind the Rab5 exchange factor rabex-5.

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^* This work was supported by Medical Research Council Grants G117/153, G9630910, and G9533795MA and by Biotechnology and Biological Sciences Research Council Grant C05969.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 44-161-275-7846; Fax: 44-161-275-5082; E-mail: pwoodman@fs1.scg.man.ac.uk.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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