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Molecular and Cellular Biology, April 2007, p. 2476-2485, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01721-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Substrate Recognition by AAA+ ATPases: Distinct Substrate Binding Modes in ATP-Dependent Protease Yme1 of the Mitochondrial Intermembrane Space{triangledown}

Martin Graef, Georgeta Seewald, and Thomas Langer*

Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany

Received 12 September 2006/ Returned for modification 27 November 2006/ Accepted 16 January 2007

The energy-dependent proteolysis of cellular proteins is mediated by conserved proteolytic AAA+ complexes. Two such machines, the m- and i-AAA proteases, are present in the mitochondrial inner membrane. They exert chaperone-like properties and specifically degrade nonnative membrane proteins. However, molecular mechanisms of substrate engagement by AAA proteases remained elusive. Here, we define initial steps of substrate recognition and identify two distinct substrate binding sites in the i-AAA protease subunit Yme1. Misfolded polypeptides are recognized by conserved helices in proteolytic and AAA domains. Structural modeling reveals a lattice-like arrangement of these helices at the surface of hexameric AAA protease ring complexes. While helices within the AAA domain apparently play a general role for substrate binding, the requirement for binding to surface-exposed helices within the proteolytic domain is determined by the folding and membrane association of substrates. Moreover, an assembly factor of cytochrome c oxidase, Cox20, serves as a substrate-specific cofactor during proteolysis and modulates the initial interaction of nonassembled Cox2 with the protease. Our findings therefore reveal the existence of alternative substrate recognition pathways within AAA proteases and shed new light on molecular mechanisms ensuring the specificity of proteolysis by energy-dependent proteases.

* Corresponding author. Mailing address: Institut für Genetik, Universität zu Köln, Zülpicher Str. 47, 50674 Köln, Germany. Phone: 49 221 470 4876. Fax: 49 221 470 6749. E-mail: Thomas.Langer{at}uni-koeln.de.

{triangledown} Published ahead of print on 29 January 2007.

Molecular and Cellular Biology, April 2007, p. 2476-2485, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01721-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tatsuta, T. (2009). Protein Quality Control in Mitochondria. J Biochem 146: 455-461 [Abstract] [Full Text]  
  • Fiumera, H. L., Dunham, M. J., Saracco, S. A., Butler, C. A., Kelly, J. A., Fox, T. D. (2009). Translocation and Assembly of Mitochondrially Coded Saccharomyces cerevisiae Cytochrome c Oxidase Subunit Cox2 by Oxa1 and Yme1 in the Absence of Cox18. Genetics 182: 519-528 [Abstract] [Full Text]  
  • Dunn, C. D., Tamura, Y., Sesaki, H., Jensen, R. E. (2008). Mgr3p and Mgr1p Are Adaptors for the Mitochondrial i-AAA Protease Complex. Mol. Biol. Cell 19: 5387-5397 [Abstract] [Full Text]  


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