Abstract

The principal aim of the previous grant was to use a combination of biophysical and computational techniques to evaluate the key features in the folding/misfolding of the 17 KD beta protein interleukin-1beta (IL-1beta). We have established that the slow folding of this beta-trefoil protein is largely controlled by """"""""topological frustration"""""""". During this time period we also became interested in understanding the role conformational dynamics plays in the biological function of this family of proteins. The change in the Title of the grant from """"""""Investigation of the Folding Mechanism of a Beta Protein"""""""" to """"""""Investigation of the Functional/Folding Landscapes of the IL-1 Family"""""""" reflect this change in research focus. In addition, we have added Dr. Jose Onuchic as a co-Pi on this proposal we have established an integrated experimental/theoretical approach towards the questions we wish to address. It is apparent that the regulation of the processing of IL-1beta is of central importance in bacterial infection and septic shock;autoimmune diseases and some cancers1-8. Yet, little is known about the molecular requirements for processing and maturation of IL-1beta. The goals of the research outlined in this proposal are directed towards (a) investigating the interplay of the functional/folding landscapes within this family of proteins (b) understanding the structural basis for cleavage of the 31 KD precursor protein;(c) the structural characterization of the 31 KD precursor protein and the 24 KD partially cleaved protein;(d) understanding the role of the presequences in destabilizing the fold of the mature 17 KD protein. In summary, our goals are to look at the functional landscapes for related proteins, to develop methods for understanding the receptor binding and signal transmission by analyzing the energy landscapes for the cytokine agonist and antagonist receptor complexes, and exploring the conformational changes that accompany the processing of prolL-1beta from the inactive partially structured state to the active, mature IL-1beta. These studies are of both fundamental importance in understanding protein recognition and activity as well as of fundamental biological importance in understanding the conformational processes that regulate the activation of prolL-1beta.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054038-12
Application #
7596959
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Wehrle, Janna P
Project Start
1996-08-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
12
Fiscal Year
2009
Total Cost
$292,907
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