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.
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.
|Morgan, Brittany R; Zitzewitz, Jill A; Massi, Francesca (2017) Structural Rearrangement upon Fragmentation of the Stability Core of the ALS-Linked Protein TDP-43. Biophys J 113:540-549|
|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|
|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|
|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 108:1503-1515|
|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|
|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:|
|Laine, Jennifer M; Amat, Miguel; Morgan, Brittany R et al. (2014) Insight into the allosteric mechanism of Scapharca dimeric hemoglobin. Biochemistry 53:7199-210|
|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|