Molcular chaperones are conserved proteins that modulate intracellular protein folding. They bind to unfolded or partially folded polypeptides preventing misfolding and aggregation and promote folding, translocation, and the assembly and disassembly of multiprotein structures. A single cells can express a variety of chaperones, including representatives of the Hsp70, Hsp90 and Hsp60 families. These chaperones differ in their substrate preferences, oligomeric state, mode of action, and in eukaryotic organisms, their subcellular location. Among the chaperones, the Hsp70 family is of particular interest. Both prokaryotic and eukaryotic organisms have multiple Hsp70 proteins, and these proteins function in every cellular compartment of the eukaryotic cell. Each Hsp70 has a conserved 45 kD N-terminal ATPase domain followed by a 18 kD peptide binding domain and a less conserved C-terminal region. The X-ray structures of the two conserved domains have been determined separately, but there is no crystal structure of an intact Hsp70. Hsp70 proteins function in concert with a cochaperone, called DnaJ or Hsp40, which modulates the ATPase and substrate binding activities of Hsp70. Cells contain multiple DnaJ family members and, in some cases, a specific DnaJ is required for a particular Hsp70 to function. Despite the key role of DnaJ in Hsp70 function, little is known about how Hsp70 interacts with DnaJ at the level of structure. I propose to use Computer Graphics Lab facilities for modeling of Hsp70-DnaJ complex based on our recent finding that DnaJ binds to two sites in the E. coli Hsp70 protein, DnaK; one in its N- terminal ATPase domain and a second in its C-terminal peptide binding domain. Structural modeling will represent an important step forward in understanding both the functional regulation of Hsp70 by its co-chaperone DnaJ and many human diseases including bacterial infections, amylodosis, autoimmune isease and cancer that are involved in the function of Hsp70/DnaJ chaperone machine.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-21
Application #
6280302
Study Section
Project Start
1998-07-01
Project End
1999-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2018) Relaxation of structural constraints during Amicyanin unfolding. J Inorg Biochem 179:135-145
Alamo, Lorenzo; Pinto, Antonio; Sulbarán, Guidenn et al. (2018) Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease. Biophys Rev 10:1465-1477
Viswanath, Shruthi; Chemmama, Ilan E; Cimermancic, Peter et al. (2017) Assessing Exhaustiveness of Stochastic Sampling for Integrative Modeling of Macromolecular Structures. Biophys J 113:2344-2353
Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219
Portioli, Corinne; Bovi, Michele; Benati, Donatella et al. (2017) Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J Biomed Mater Res A 105:847-858
Alamo, Lorenzo; Koubassova, Natalia; Pinto, Antonio et al. (2017) Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. Biophys Rev 9:461-480
Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A et al. (2017) Enhanced potency of bivalent small molecule gp41 inhibitors. Bioorg Med Chem 25:408-420
Sato, Daisuke; Shannon, Thomas R; Bers, Donald M (2016) Sarcoplasmic Reticulum Structure and Functional Properties that Promote Long-Lasting Calcium Sparks. Biophys J 110:382-390
Towse, Clare-Louise; Rysavy, Steven J; Vulovic, Ivan M et al. (2016) New Dynamic Rotamer Libraries: Data-Driven Analysis of Side-Chain Conformational Propensities. Structure 24:187-199

Showing the most recent 10 out of 508 publications