Regulation of gene expression is central to efficient biological function. Two key aspects of this process are the synthesis of mRNA (transcription) and control of its stability. The goal of this proposal is to understand how an important class of proteins, the CCCH zinc finger proteins of the tristetraprolin (TTP) family, recognizes and binds to mRNA to promote its degradation. This process provides an important mechanism for reducing the synthesis of key cytokines and growth factors that regulate inflammation and the initiation and progression of cancer. To understand the function and regulation of TTP in the cell we will use an integrated approach that combines NMR spectroscopy, computer simulation, biochemical and in vivo experiments. Our detailed biophysical and biochemical characterizations of TTP-mRNA interactions will determine the mechanism of TTP-mediated mRNA destabilization that is relevant for cancer and inflammation.

Public Health Relevance

TTP is an important protein for limiting the production of cytokines and growth factors involved in tumor growth and progression and in chronic inflammation. This study will improve our understanding of the mechanisms by which TTP regulates the production of proteins related to these diseases, and will give us a new understanding of the molecular basis of cancer and chronic inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098763-04
Application #
8727062
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Preusch, Peter
Project Start
2011-09-15
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655
Deveau, Laura M; Massi, Francesca (2016) Three Residues Make an Evolutionary Switch for Folding and RNA-Destabilizing Activity in the TTP Family of Proteins. ACS Chem Biol 11:435-43
Tavella, Davide; Deveau, Laura M; Whitfield, Troy W et al. (2016) Structural Basis of the Disorder in the Tandem Zinc Finger Domain of the RNA-Binding Protein Tristetraprolin. J Chem Theory Comput 12:4717-4725
Morgan, Brittany R; Deveau, Laura M; Massi, Francesca (2015) Probing the structural and dynamical effects of the charged residues of the TZF domain of TIS11d. Biophys J 108:1503-15
Zearfoss, N Ruth; Deveau, Laura M; Clingman, Carina C et al. (2014) A conserved three-nucleotide core motif defines Musashi RNA binding specificity. J Biol Chem 289:35530-41
Laine, Jennifer M; Amat, Miguel; Morgan, Brittany R et al. (2014) Insight into the allosteric mechanism of Scapharca dimeric hemoglobin. Biochemistry 53:7199-210
Clingman, Carina C; Deveau, Laura M; Hay, Samantha A et al. (2014) Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite. Elife 3:
Gangadhara, Basavanapura N; Laine, Jennifer M; Kathuria, Sagar V et al. (2013) Clusters of branched aliphatic side chains serve as cores of stability in the native state of the HisF TIM barrel protein. J Mol Biol 425:1065-81