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Function and regulation of the universally conserved heat shock proteins

English title Function and regulation of the universally conserved heat shock proteins
Applicant Georgopoulos Costa Panos
Number 114063
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Molecular Biology
Start/End 01.10.2006 - 30.09.2007
Approved amount 256'247.00
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Lay Summary (English)

Lay summary
1.Goals of research project
The overall goal of our research program is a better understanding of the in vivo protein folding process. Normally, a properly folded protein, such as an enzyme, has its hydrophobic (water « afraid ») amino acid residues buried deeply inside its three-dimensional structure. However, as the newly born polypeptide chain emerges from the ribosome, these hydrophobic amino acid sequences are transiently exposed to the aqueous cellular environment, before the full chain is finished and properly folded. Because of their tendency to “stick together”, such hydrophobic sequences can lead to premature and abnormal aggregation, either within a single protein or among several proteins. To deal with this problem, organisms have evolved the so-called “molecular chaperone” (also known as “heat shock”) class of proteins, whose primary goal is to transiently bind to short, hydrophobic segments of nascent chains or unfolded proteins, thus preventing them from premature aggregation. By such cycles of binding and release, molecular chaperones “guide” unfolded polypeptides to their final, stably folded state.

2.Importance of the project
Because of its ability to both prevent protein aggregation and disaggregate protein aggregates, overproduction of the Hsp70 molecular chaperone machine in the cell has been shown to modulate a variety of important intracellular processes, such as apoptosis, cellular transformation, tumor immunogenecity, as well as various important human diseases caused by abnormal conformational protein states, such as Parkinson’s and Huntington’s diseases. Our own work has shown that mutations in the human Hsp60 gene lead to a form of human spastic paraplegia disease. Thus, a better understanding of how molecular chaperones help to fold the nascent polypeptide chains is necessary to better understand intracellular protein aggregation, and ultimately cure these human diseases.

3. Research Projects
(a) We have recently shown that E. coli secB null mutants exhibit a strong cold-sensitive phenotype. We are pursuing the identification of high-copy or loss-of-function suppressors which restore bacterial growth at the otherwise lethal temperature of 14-16°C. The effect of these suppressors on overall intracellular protein aggregation in the secB null mutant will be studied.
(b) We are investigating the nature of various suppressor mutations in the dnaK gene which restore growth of the E. coli grpE280 temperature-sensitive mutant.
(c) We have recently shown that a “pseudo-T4” phage, RB43, encodes a bona fide dnaJ gene homolog. We are studying the role of this gene in RB43 growth with the appropriate genetic and biochemical techniques.
(d) We are studying how various mutations in the T4-, RB43- or RB49- cochaperone gene 31 homologs endow them with the unique ability to plaque on some of our various E. coli mutant hosts.
(e) We recently discovered a small open reading frame (ORF) encoded by various virulent phage which modulates the GroEL chaperone machine. By using appropriate in vivo and in vitro biochemical experiments, we will seek to understand the molecular mechanism by which this small ORF modulates GroEL chaperone activity.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants


Associated projects

Number Title Start Funding scheme
65403 Function and regulation of the universally conserved heat shock response 01.10.2001 Project funding (Div. I-III)