Molecular Biophysics I
2005
Session #10

Molecular Chaperones
and
Protein Un-folding & Dis-aggregation

April 06, 2005
BioMed 155-2
1:00 p.m. - 3:50 p.m.

To this point, we have viewed the role of molecular chaperones primarily in the context of protein folding, i.e. to minimize the possibility of aggregation by sequential binding, and then controlled release, of exposed, aggregation-prone sequences.

However, several important cellular processes require that polypeptide chains be un-folded...after they were once successfully folded! Do molecular chaperones have a role in this unfolding process?

In addition, particularly under conditions of cellular stress, the chaperone network can be temporarily overwhelmed, and protein aggregates can form. Are there molecular chaperones that can mediate the disaggregation of already-formed protein aggregates?

The answer to both questions above is yes; both such activities have now been identified and partially characterized in cells across the biological spectrum.

In this session we shall consider protein unfolding in general (the review by Prakash & Matouschek), and and unfolding as a possible component in chaperone-mediated protein disaggregation in particular.

Student Assignments

The first four references in the list below are review articles that pertain to the session focus papers (last four papers). All students should obtain copies of the reviews; we'll go over each briefly in class. Reference #4 by Arthur Horwich is a comment paper on the results from the Bukau/Mogk labs as reported by Weibezahn et al (reference #8). As before, refer to the Student Roster for your student number.

•  Parsell et al (Ref. #5): Student #1: Figs. 1 & 2; Student #2: Figs. 3 & 4. (Note: A scanned-pdf version of this paper is available on the UAMS Library eReserves site.);

•  Glover & Lindquist (Ref. #6): Student #3: Figs. 1, 2, & 4 ONLY;

•  Goloubinoff et al (Ref. #7): Student #4: Fig. 1; Student #5: Figs. 3, 4, & 5;

•  Weibezahn et al paper in Cell (Ref. #8):
      Student #6: Fig. 1;
      Student #7: Fig. 2
      Student #8: Fig. 3
      Student #9: Fig. 4
      Student #10: Fig. 5

References

Reviews

   1.   Prakash,S. and Matouschek,A. (2004). Protein unfolding in the cell. Trends Biochem. Sci. 29, 593-600.

   2.   Weibezahn,J., Bukau,B., and Mogk,A. (2004). Unscrambling an egg: protein disaggregation by AAA+ proteins. Microb. Cell Fact. 3, 1.

   3.   Mogk,A. and Bukau,B. (2004). Molecular chaperones: Structure of a protein disaggregase. Current Biology 14, R78-R80.

   4.   Horwich,A.L. (2004). Chaperoned protein disaggregation--the ClpB ring uses its central channel. Cell 119, 579-581.

Data Papers

   5.   Parsell,D.A., Kowal,A.S., Singer,M.A., and Lindquist,S. (1994). Protein disaggregation mediated by heat-shock protein Hsp104. Nature 372, 475-478.

   6.   Glover,J.R. and Lindquist,S. (1998). Hsp104, Hsp70, and Hsp40 - A Novel Chaperone System that Rescues Previously Aggregated Proteins. Cell 94, 73-82.

   7.   Goloubinoff,P., Mogk,A., Ben Zvi,A.P., Tomoyasu,T., and Bukau,B. (1999). Sequential mechanism of solubilization and refolding of stable protein aggregates by a bichaperone network. Proc. Natl. Acad. Sci. USA 96, 13732-13737.

   8.   Weibezahn,J. et al. (2004). Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB. Cell 119, 653-665.