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J. Biol. Chem., Vol. 281, Issue 7, 4156-4163, February 17, 2006

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The Cysteine-rich Secretory Protein Domain of Tpx-1 Is Related to Ion Channel Toxins and Regulates Ryanodine Receptor Ca²⁺ Signaling^*

Gerard M. Gibbs, Martin J. Scanlon, James Swarbrick, Suzanne Curtis^¶, Esther Gallant^¶, Angela F. Dulhunty^¶, and Moira K. O'Bryan^||1

From the Monash Institute of Medical Research, the ^||Australian Research Council Centre of Excellence in Biotechnology and Development, and the Department of Medicinal Chemistry, Monash University, Clayton, 3168 Melbourne, Victoria and ^¶John Curtain School of Medical Research, the Australian National University, Canberra, Australian Capital Territory 2601, Australia

The cysteine-rich secretory proteins (Crisp) are predominantly found in the mammalian male reproductive tract as well as in the venom of reptiles. Crisps are two domain proteins with a structurally similar yet evolutionary diverse N-terminal domain and a characteristic cysteine-rich C-terminal domain, which we refer to as the Crisp domain. We presented the NMR solution structure of the Crisp domain of mouse Tpx-1, and we showed that it contains two subdomains, one of which has a similar fold to the ion channel regulators BgK and ShK. Furthermore, we have demonstrated for the first time that the ion channel regulatory activity of Crisp proteins is attributed to the Crisp domain. Specifically, the Tpx-1 Crisp domain inhibited cardiac ryanodine receptor (RyR) 2 with an IC₅₀ between 0.5 and 1.0 µM and activated the skeletal RyR1 with an AC₅₀ between 1 and 10 µM when added to the cytoplasmic domain of the receptor. This activity was nonvoltage-dependent and weakly voltage-dependent, respectively. Furthermore, the Tpx-1 Crisp domain activated both RyR forms at negative bilayer potentials and showed no effect at positive bilayer potentials when added to the luminal domain of the receptor. These data show that the Tpx-1 Crisp domain on its own can regulate ion channel activity and provide compelling evidence for a role for Tpx-1 in the regulation of Ca²⁺ fluxes observed during sperm capacitation.

Received for publication, June 23, 2005 , and in revised form, November 8, 2005.

^* This work was supported by National Health and Medical Research Council Grant 334011 and Australian Research Council Grants CE0348239 (to M. K. O. B.) and DP0557780 (to A. F. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2A05) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ Recipient of a senior research fellowship from Monash University. To whom correspondence should be addressed: Monash Institute of Medical Research, Monash University, 27-31 Wright St., Clayton, 3168, Victoria, Australia. Tel.: 613-9594-7127; Fax: 613-9594-7114; E-mail: Moira.OBryan{at}med.monash.edu.au.

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