Zinc induced folding is essential for TIM15 activity as an mtHsp70 chaperone

Hugo Fraga, Elena Papaleo, Sonia Vega, Adrián Velazquez-Campoy, Salvador Ventura

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Background: TIM15/Zim17 in yeast and its mammalian ortholog Hep are Zn 2 + finger (Cys4) proteins that assist mtHsp70 in protein import into the mitochondrial matrix. Methods: Here we characterized the Zn2 + induced TIM15 folding integrating biophysical and computational approaches. Results: TIM15 folding occurs from an essentially unstructured conformation to a Zn2 +-coordinated protein in a fast and markedly temperature-dependent process. Moreover, we demonstrate unambiguously that Zn2 + induced TIM15 folding is essential for its role as mtHsp70 chaperone since in the unstructured apo state TIM15 does not bind to mtHsp70 and is unable to prevent its aggregation. Molecular dynamics simulations help to understand the crucial role of Zn2 + in promoting a stable and functional 3D architecture in TIM15. It is shown that the metal ion, through its coordinating cysteine residues, can mediate relevant long-range effects with the interaction interface for mtHsp70 coupling thus folding and function. Conclusions: Zn2 + induced TIM15 folding is essential for its function and likely occurs in mitochondrial matrix where high concentrations of Zn2 + were reported. General significance: The combination of experimental and computational approaches presented here provide an integrated structural, kinetic and thermodynamic view of the folding of a mitochondrial zinc finger protein, which might be relevant to understand the organelle import of proteins sharing this fold. © 2012 Elsevier B.V. © 2012 Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)2139-2149
JournalBiochimica et Biophysica Acta - General Subjects
Volume1830
DOIs
Publication statusPublished - 1 Jan 2013

Keywords

  • Mitochondrion
  • Protein folding
  • Protein translocation
  • TIM15
  • Zinc finger

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