Abstract

The principal aim of the original R29 proposal was to use a combination of biophysical techniques to evaluate the key features involved in the early and late steps in the productive (native) and nonproductive (inclusion body) folding pathways of the all b protein IL-lb. The goals of the research outlined in this proposal are directed towards defining the topological/structural determinants in the folding and aggregation reactions of IL-lb and the role conformational changes play in the biological function of the cytokine. Our research efforts are directed towards a comprehensive approach to an understanding of the role topology plays in the folding and function of this class of proteins. We plan to (a) explore the role chain-connectivity, specific side-chain interactions and structural waters play in orchestrating the folding reaction, (b) explore the role of the unfolded ensemble in mediating aggregation reactions and (c) analyze structurally the conformation of the partially folded pro-protein, We will use a combination of biophysical techniques towards these goals including heteronuclear NMR, hydrogen/deuterium exchange, mass spectrometric, computational, and optical spectroscopies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054038-08
Application #
6782606
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Wehrle, Janna P
Project Start
1996-08-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
8
Fiscal Year
2004
Total Cost
$246,736
Indirect Cost

  Institution

Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Tamir, Sagi; Paddock, Mark L; Darash-Yahana-Baram, Merav et al. (2015) Structure-function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease. Biochim Biophys Acta 1853:1294-315
Tamir, Sagi; Rotem-Bamberger, Shahar; Katz, Chen et al. (2014) Integrated strategy reveals the protein interface between cancer targets Bcl-2 and NAF-1. Proc Natl Acad Sci U S A 111:5177-82
Tamir, Sagi; Eisenberg-Domovich, Yael; Conlan, Andrea R et al. (2014) A point mutation in the [2Fe-2S] cluster binding region of the NAF-1 protein (H114C) dramatically hinders the cluster donor properties. Acta Crystallogr D Biol Crystallogr 70:1572-8
Capraro, Dominique T; Lammert, Heiko; Heidary, David K et al. (2013) Altered backbone and side-chain interactions result in route heterogeneity during the folding of interleukin-1? (IL-1?). Biophys J 105:975-83
Hailey, Kendra L; Capraro, Dominique T; Barkho, Sulyman et al. (2013) Allosteric switching of agonist/antagonist activity by a single point mutation in the interluekin-1 receptor antagonist, IL-1Ra. J Mol Biol 425:2382-92
Sohn, Yang-Sung; Tamir, Sagi; Song, Luhua et al. (2013) NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth. Proc Natl Acad Sci U S A 110:14676-81
Andrews, Benjamin T; Capraro, Dominique T; Sulkowska, Joanna I et al. (2013) Hysteresis as a Marker for Complex, Overlapping Landscapes in Proteins. J Phys Chem Lett 4:180-188
Baxter, Elizabeth Leigh; Zuris, John A; Wang, Charles et al. (2013) Allosteric control in a metalloprotein dramatically alters function. Proc Natl Acad Sci U S A 110:948-53
Tamir, Sagi; Zuris, John A; Agranat, Lily et al. (2013) Nutrient-deprivation autophagy factor-1 (NAF-1): biochemical properties of a novel cellular target for anti-diabetic drugs. PLoS One 8:e61202
Barkho, Sulyman; Pierce, Levi C T; McGlone, Maria L et al. (2013) Distal loop flexibility of a regulatory domain modulates dynamics and activity of C-terminal SRC kinase (csk). PLoS Comput Biol 9:e1003188

Showing the most recent 10 out of 31 publications