Article
- The EMBO Journal (2006) 25, 1720 - 1729
- doi:10.1038/sj.emboj.7601058
Published online: 6 April 2006
Subject Category:
Glycine–alanine repeats impair proper substrate unfolding by the proteasome
Martin A Hoyt1,a, Judith Zich1,a, Junko Takeuchi1, Mingsheng Zhang1, Cedric Govaerts2 and Philip Coffino1
- Department of Microbiology and Immunology, University of California, San Francisco, CA, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA
Correspondence to:
Philip Coffino, Department of Microbiology and Immunology, UCSF, 513 Parnassus Avenue, San Francisco, CA 94143-0414, USA. Tel.: +1 415 476 1783; E-mail: Philip.Coffino@ucsf.edu
aThese authors contributed equally to this work
Received 20 September 2005; Accepted 1 March 2006
Abstract
Proteasome ATPases unravel folded proteins. Introducing a sequence containing only glycine and alanine residues (GAr) into substrates can impair their digestion. We previously proposed that a GAr interferes with the unfolding capacity of the proteasome, leading to partial degradation of products. Here we tested that idea in several ways. Stabilizing or destabilizing a folded domain within substrate proteins changed GAr-mediated intermediate production in the way predicted by the model. A downstream folded domain determined the sites of terminal proteolysis. The spacing between a GAr and a folded domain was critical for intermediate production. Intermediates containing a GAr did not remain associated with proteasomes, excluding models whereby retained GAr-containing proteins halt further processing. The following model is supported: a GAr positioned within the ATPase ring reduces the efficiency of coupling between nucleotide hydrolysis and work performed on the substrate. If this impairment takes place when unfolding must be initiated, insertion pauses and proteolysis is limited to the portion of the substrate that has already entered the catalytic chamber of the proteasome.
Keywords:
- ATPase,
- Gly–Ala repeat,
- proteasome,
- protein structure,
- protein unfolding
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