2A05

The cysteine-rich secretory protein domain of Tpx-1 is related to ion channel toxins and regulates Ryanodine receptor Ca2+ signaling

Summary for 2A05

• Entry DOI: 10.2210/pdb2a05/pdb
• NMR Information: BMRB: 6740
• Descriptor: Cysteine-rich secretory protein-2 (1 entity in total)
• Functional Keywords: 3 alpha helices, 5 disulphide bonds, 2 domains, signaling protein
• Biological source: Mus musculus (house mouse)
• Cellular location: Secreted (Probable): P16563
• Total number of polymer chains: 1
• Total formula weight: 6121.93

Authors

Gibbs, G.M.,Scanlon, M.J.,Swarbrick, J.,Curtis, S.,Dulhunty, A.F.,O'Bryan, M.K. (deposition date: 2005-06-15, release date: 2006-01-17, Last modification date: 2024-10-16)

Primary citation

Gibbs, G.M.,Scanlon, M.J.,Swarbrick, J.,Curtis, S.,Gallant, E.,Dulhunty, A.F.,O'Bryan, M.K.
The cysteine-rich secretory protein domain of Tpx-1 is related to ion channel toxins and regulates ryanodine receptor Ca2+ signaling.
J.Biol.Chem., 281:4156-4163, 2006

PubMed Abstract: 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 IC(50) between 0.5 and 1.0 microM and activated the skeletal RyR1 with an AC(50) between 1 and 10 microM 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 Ca(2+) fluxes observed during sperm capacitation.

PubMed: 16339766
DOI: 10.1074/jbc.M506849200

Experimental method

SOLUTION NMR