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J. Biol. Chem., Vol. 282, Issue 26, 18694-18701, June 29, 2007

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Awaking TIM22, a Dynamic Ligand-gated Channel for Protein Insertion in the Mitochondrial Inner Membrane^*

Pablo M. V. Peixoto¹, Fernando Graña, Teresa J. Roy, Cory D. Dunn^¶, Montaña Flores, Robert E. Jensen^¶, and María Luisa Campo²

From the Department of Biochemistry and Molecular Biology and the Department of Animal Medicine, University of Extremadura, 10071 Cáceres, Spain and ^¶Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Aqueous channels are at the core of the translocase of the outer membrane (TOM) and the translocase of the inner membrane for the transport of preproteins (TIM23), the translocases mediating the transport of proteins across the outer and inner mitochondrial membranes. Yet, the existence of a channel associated to the translocase of the inner membrane for the insertion of multitopic protein (TIM22) complex has been arguable, as its function relates to the insertion of multispanning proteins into the inner membrane. For the first time, we report conditions for detecting a channel activity associated to the TIM22 translocase in organelle, i.e. intact mitoplasts. An internal signal peptide in the intermembrane space of mitochondria is a requisite to inducing this channel, which is otherwise silent. The channel showed slightly cationic and high conductance activity of 1000 pS with a predominant half-open substate. Despite their different composition, the channels of the three mitochondrial translocases were thus remarkably similar, in agreement with their common task as pores transiently trapping proteins en route to their final destination. The opening of the TIM22 channel was a step-up process depending on the signal peptide concentration. Interestingly, low membrane potentials kept the channel fully open, providing a threshold level of the peptide is present. Our results portray TIM22 as a dynamic channel solely active in the presence of its cargo proteins. In its fully open conformation, favored by the combined action of internal signal peptide and low membrane potential, the channel could embrace the in-transit protein. As insertion progressed and initial interaction with the signal peptide faded, the channel would close, sustaining its role as a shunt that places trapped proteins into the membrane.

Received for publication, January 26, 2007 , and in revised form, March 22, 2007.

^* This research was supported by a grant from Junta de Extremadura 2PR04B005. 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 Recipient of a Coordenação de Aperfeiçoamento de Pessoal de Nível Superior fellowship (1047019) from the Brazilian Ministry of Education and Science.

² To whom correspondence should be addressed: Faculty of Veterinary Sciences, Dept. of Biochemistry and Molecular Biology, University of Extremadura, Avda. de la Universidad s/n, 10071 Cáceres, Spain. Tel.: 927-257-119; Fax: 927-257-110; E-mail: mlcampo{at}unex.es.

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