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Vol. 13, Issue 5, 1439-1448, May 2002

Competition of Spontaneous Protein Folding and Mitochondrial Import Causes Dual Subcellular Location of Major Adenylate Kinase

Gertrud Strobel, Alfred Zollner,^* Michaela Angermayr, and Wolfhard Bandlow

Institut für Genetik und Mikrobiologie der Universität München, D-80638 Munich, Germany

Sorting of cytoplasmically synthesized proteins to their target compartments usually is highly efficient so that cytoplasmic precursor pools are negligible and a particular gene product occurs at one subcellular location only. Yeast major adenylate kinase (Adk1p/Aky2p) is one prominent exception to this rule. In contrast to most mitochondrial proteins, only a minor fraction (6-8%) is taken up into the mitochondrial intermembrane space, whereas the bulk of the protein remains in the cytosol in sequence-identical form. We demonstrate that Adk1p/Aky2p uses a novel mechanism for subcellular partitioning between cytoplasm and mitochondria, which is based on competition between spontaneous protein folding and mitochondrial targeting and import. Folding is spontaneous and rapid and can dispense with molecular chaperons. After denaturation, enzymatic activity of Adk1p/Aky2p returns within a few minutes and, once folded, the protein is thermally and proteolytically very stable. In an uncoupled cell-free organellar import system, uptake of Adk1p/Aky2p is negligible, but can be improved by previous chaotropic denaturation. Import ensues independently of Hsp70 or membrane potential. Thus, nascent Adk1p/Aky2p has two options: either it is synthesized to completion and folds into an enzymatically active import-incompetent conformation that remains in the cytosol; or, during synthesis and before commencement of significant tertiary structure formation, it reaches a mitochondrial surface receptor and is internalized.

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^* Present address: Biomax, Am Klopferspitz, D-82152 Martinsried, Germany.

Corresponding author. E-mail address: W.Bandlow{at}lrz.uni-muenchen.de.

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Molecular Biology of the Cell
Vol. 13, 1439-1448, May 2002
Copyright © 2002 by The American Society for Cell Biology

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