Journal
MOLECULAR CELL
Volume 29, Issue 4, Pages 441-450Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2008.02.002
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Funding
- NIAID NIH HHS [R01 AI016892-29, AI-16892, R01 AI016892, R01 AI016892-28] Funding Source: Medline
- NIGMS NIH HHS [R01 GM049224-16, R01 GM049224] Funding Source: Medline
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ClpX, an archetypal proteolytic AAA+ unfoldase, must engage the ssrA tags of appropriate substrates prior to ATP-dependent unfolding and translocation of the denatured polypeptide into ClpP for degradation. Here, specificity-transplant and disulfide-crosslinking experiments reveal that the ssrA tag interacts with different loops that form the top, middle, and lower portions of the central channel of the ClpX hexamer. Our results support a two-step binding mechanism, in which the top loop serves as a specificity filter and the remaining loops form a binding site for the peptide tag relatively deep within the pore. Crosslinking experiments suggest a staggered arrangement of pore loops in the hexamer and nucleotide-dependent changes in pore-loop conformations. This mechanism of initial tag binding would allow ATIP-dependent conformational changes in one or more pore loops to drive peptide translocation, force unfolding, and mediate threading of the denatured protein through the ClpX pore.
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