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doi:10.1534/genetics.106.056820
A more recent version of this article appeared on June 1, 2006.
REGULAR RESEARCH PAPERS |
N-terminal domain of yeast Hsp104 chaperone is dispensable for thermotolerance and prion propagation but necessary for curing prions by Hsp104 overexpression
Daniel C. Masison 1* and Guo-Chiuan Hung 1
1 National Institutes of Health
* To whom correspondence should be addressed. E-mail: masisond{at}helix.nih.gov.
Submitted on February 7, 2006
Revised on March 5, 2006
Accepted on 24 March 2006
Hsp104 is a hexameric protein chaperone that resolubilizes stress-damaged proteins from aggregates. Hsp104 promotes [PSI+] prion propagation by breaking prion aggregates, which propagate as amyloid fibers, into more numerous prion "seeds". Inactivating Hsp104 cures cells of [PSI+] and other amyloid-like yeast prions. Overexpressing Hsp104 also eliminates [PSI+], presumably by completely resolubilizing prion aggregate. Inexplicably, however, excess Hsp104 does not cure the other prions. Here, we identify mis-sense mutations in Hsp104's amino-terminal domain (NTD), which is conserved among Hsp100 proteins but whose function is unknown, that improve [PSI+] propagation. Hsp104
147, engineered to lack the NTD, supported [PSI+] and functioned normally in thermotolerance and protein disaggregation. Hsp104147 failed to cure [PSI+] when overexpressed, however, implying that excess Hsp104 does not eliminate [PSI+] by direct dissolution of prion aggregates. Curing of [PSI+] by overexpressing catalytically inactive Hsp104 (Hsp104KT), which interferes with endogenous Hsp104, did not require the NTD. We further find Hsp104 mutants defective in threading peptides through the hexamer pore had reduced ability to support [PSI+] in proportion to protein resolubilization defects, suggesting that [PSI+] propagation depends on this threading and that Hsp104 "breaks" prion aggregates by extracting protein monomers from the amyloid fibers.
Key Words: Hsp104, Hsp70, chaperone, prion
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