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Originally published In Press as doi:10.1074/jbc.M508210200 on October 27, 2005

J. Biol. Chem., Vol. 280, Issue 52, 43218-43223, December 30, 2005
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TRP-ML1 Is a Lysosomal Monovalent Cation Channel That Undergoes Proteolytic Cleavage*

Kirill Kiselyov{ddagger}§, Jin Chen{ddagger}, Youssef Rbaibi§, Daniel Oberdick§, Sandra Tjon-Kon-Sang{ddagger}, Nikolay Shcheynikov{ddagger}, Shmuel Muallem{ddagger}1, and Abigail Soyombo{ddagger}

From the {ddagger}Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 and the §Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Mutations in the gene MCOLN1 coding for the TRP (transient receptor potential) family ion channel TRP-ML1 lead to the lipid storage disorder mucolipidosis type IV (MLIV). The function and role of TRP-ML1 are not well understood. We report here that TRP-ML1 is a lysosomal monovalent cation channel. Both native and recombinant TRP-ML1 are cleaved resulting in two products. Recombinant TRP-ML1 is detected as the full-length form and as short N- and C-terminal forms, whereas in native cells mainly the cleaved N and C termini are detected. The N- and C-terminal fragments of TRP-ML1 were co-immunoprecipitated from cell lysates and co-eluted from a Ni2+ column. TRP-ML1 undergoes proteolytic cleavage that is inhibited by inhibitors of cathepsin B (CatB) and is altered when TRP-ML1 is expressed in CatB-/- cells. N-terminal sequencing of purified C-terminal fragment of TRP-ML1 expressed in Sf9 cells indicates a cleavage site at Arg200 {downarrow} Pro201. Consequently, the conserved R200H mutation changed the cleavage pattern of TRP-ML1. The cleavage inhibited TRP-ML1 channel activity. This work provides the first example of inactivation by cleavage of a TRP channel. The significance of the cleavage to the function of TRP-ML1 is under investigation.

Received for publication, July 27, 2005 , and in revised form, October 25, 2005.

* This work was supported by National Institutes of Health Grants DE12309 and DK38938 (to S. M.), by a grant from the Mucolipidosis Foundation (to A. S.), and by the Pittsburgh Life Science Greenhouse start-up fund (to K. K.). 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.

1 To whom correspondence should be addressed: Dept. of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9040. Tel.: 214-645-6008; E-mail: shmuel.muallem{at}utsouthwestern.edu.


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