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    Francesca Massi PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-4501
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBioinformatics and Computational Biology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBioinformatics and Integrative Biology

        Overview 
        Narrative

        Academic Background

        Laurea, University of Rome “La Sapienza”, 1995
        Ph.D., Boston University , 2002
        Postdoctoral Fellow, Columbia University, 2002-2007

         

        From protein dynamics to protein function and stability using NMR spectroscopy and computer simulation.

        Proteins are flexible molecules that often undergo conformational changes to perform biological functions. For this reason, knowledge of the internal dynamics of proteins is crucial to an understanding of the details of their functions and mechanisms of action.

        The focus of my laboratory is to understand the relationship between structure, stability, and dynamics of proteins. In particular we investigate how the structure and dynamics of a protein affect molecular recognition, allostery and stability. To this end, we take a multi-disciplinary approach combining the strengths of biophysical, biochemical and in vivo techniques, with particular emphasis on solution NMR spectroscopic and computational methods.

        Specific targets of our research program:

        1.     The TTP protein family regulates cytokine mRNA turnover:  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. This process provides an important mechanism for reducing the synthesis of key cancer-related proteins, including a number of cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-3 (IL-3), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) that regulate processes that are involved in inflammation and in cancer initiation and progression. Our work is uncovering how an important class of proteins recognizes and binds to mRNA to promote its degradation.

        2.     C. elegans TZF proteins govern cell fate specification in early embryogenesis: In the early embryogenesis of C. elegans, the fates of all the founder cells are determined solely through the regulation of maternally supplied mRNA molecules, as zygotic transcription has not yet started: characterizing the mechanism of post-transcriptional mRNA regulation is fundamental, therefore, to a more complete understanding of embryogenesis. Several RNA binding proteins are necessary in this process, among them MEX-5, MEX-6, PIE-1, POS-1 and MEX-1 are all CCCH-type TZF proteins related to TTP. Mutations in the TZF domain of these proteins perturb the expression of several maternal genes, indicating that these proteins influence the stability and/or tune the translational efficiency of maternal mRNAs. It has been shown that these closely related proteins bind to RNA with different specificities, and that these differences have major implications for the biological activity of each protein. The origin of the different RNA-binding specificities is not yet understood. Our goal is to understand the factors that determine RNA-binding affinity and specificity and their role in embryogenesis.

        3.     The allosteric mechanism of Scapharca dimeric hemoglobin (HbI): Allosteric regulation is an essential function of many proteins that control a variety of different processes such as catalysis, signal transduction, and gene regulation. Structural rearrangements have historically been considered the main means of communication between different parts of a protein. Recent studies have highlighted the importance, however, of changes in protein flexibility as an effective way to mediate allosteric communication across a protein. We are characterizing the contributions of dynamics to allosteric function using a homodimeric hemoglobin that constitutes a unique system with which to probe these issues.



        Rotation Projects

        Rotation Projects

        Rotation projects are available to address the following questions:

        1. How does the lack of structure in the C-terminal zinc finger of TTP affect the activity of the protein in the cell?

        In humans, there are three members in the TTP protein family: TTP, TIS11b and TIS11d. Structural studies performed by us and others have shown that while the TZF domain of TTP is partially unstructured in the free state and folds upon binding RNA, those of TIS11d and TIS11b are always folded. We have shown that the degree of structure of the TZF domain affects the activity of the protein in cells and indicates that the protein can modulate its activity through its dynamics. We want to determine whether structural disorder is directly linked to cellular stability or protein localization

         

        1. How do mutations in the RNA-binding domain of TIS11d cause cancer?

        Several point mutation in TTP and TIS11d have been linked to cancer. In particular, point mutations in the RNA-binding domain of TIS11d are found in leukemia patients. We are currently working on the characterization of the structure, dynamics and biological activity of these mutant proteins to understand their role in the pathogenesis of cancer.

         

        1. How does HuR regulate the stability of its target mRNA?

        HuR is another protein that, like TTP, binds to AU-rich elements (ARE) in mRNAs and regulate their stability. The detailed mechanisms that determine how HuR regulates transcripts stability are poorly understood. We are investigating how binding or HuR to the 3’UTR of an mRNA leads to its stabilization.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Deveau LM, Massi F. Three Residues Make an Evolutionary Switch for Folding and RNA-Destabilizing Activity in the TTP Family of Proteins. ACS Chem Biol. 2016 Feb 19; 11(2):435-43.
          View in: PubMed
        2. Morgan BR, Deveau LM, Massi F. Probing the structural and dynamical effects of the charged residues of the TZF domain of TIS11d. Biophys J. 2015 Mar 24; 108(6):1503-15.
          View in: PubMed
        3. Laine JM, Amat M, Morgan BR, Royer WE, Massi F. Insight into the allosteric mechanism of Scapharca dimeric hemoglobin. Biochemistry. 2014 Nov 25; 53(46):7199-210.
          View in: PubMed
        4. Zearfoss NR, Deveau LM, Clingman CC, Schmidt E, Johnson ES, Massi F, Ryder SP. A conserved three-nucleotide core motif defines Musashi RNA binding specificity. J Biol Chem. 2014 Dec 19; 289(51):35530-41.
          View in: PubMed
        5. Ertekin, A; Massi, F. eMagRes. Understanding the role of conformational dynamics in protein-ligand interactions using NMR relaxation methods. 2014; 3(3):255-266.
        6. Clingman CC, Deveau LM, Hay SA, Genga RM, Shandilya SM, Massi F, Ryder SP. Allosteric inhibition of a stem cell RNA-binding protein by an intermediary metabolite. Elife. 2014 Jun 16; 3.
          View in: PubMed
        7. Gangadhara BN, Laine JM, Kathuria SV, Massi F, Matthews CR. Clusters of branched aliphatic side chains serve as cores of stability in the native state of the HisF TIM barrel protein. J Mol Biol. 2013 Mar 25; 425(6):1065-81.
          View in: PubMed
        8. Romano KP, Laine JM, Deveau LM, Cao H, Massi F, Schiffer CA. Molecular mechanisms of viral and host cell substrate recognition by hepatitis C virus NS3/4A protease. J Virol. 2011 Jul; 85(13):6106-16.
          View in: PubMed
        9. Stewart MD, Morgan B, Massi F, Igumenova TI. Probing the determinants of diacylglycerol binding affinity in the C1B domain of protein kinase Ca. J Mol Biol. 2011 May 20; 408(5):949-70.
          View in: PubMed
        10. Morgan BR, Massi F. Accurate Estimates of Free Energy Changes in Charge Mutations. J Chem Theory Comput. 2010 Jun 8; 6(6):1884-93.
          View in: PubMed
        11. Morgan BR, Massi F. A computational study of RNA binding and specificity in the tandem zinc finger domain of TIS11d. Protein Sci. 2010 Jun; 19(6):1222-34.
          View in: PubMed
        12. Ryder SP, Massi F. Insights into the structural basis of RNA recognition by STAR domain proteins. Adv Exp Med Biol. 2010; 693:37-53.
          View in: PubMed
        13. Valentine ER, Ferrage F, Massi F, Cowburn D, Palmer AG. Joint composite-rotation adiabatic-sweep isotope filtration. J Biomol NMR. 2007 May; 38(1):11-22.
          View in: PubMed
        14. Massi F, Wang C, Palmer AG. Solution NMR and computer simulation studies of active site loop motion in triosephosphate isomerase. Biochemistry. 2006 Sep 12; 45(36):10787-94.
          View in: PubMed
        15. Palmer AG, Massi F. Characterization of the dynamics of biomacromolecules using rotating-frame spin relaxation NMR spectroscopy. Chem Rev. 2006 May; 106(5):1700-19.
          View in: PubMed
        16. Massi F, Grey MJ, Palmer AG. Microsecond timescale backbone conformational dynamics in ubiquitin studied with NMR R1rho relaxation experiments. Protein Sci. 2005 Mar; 14(3):735-42.
          View in: PubMed
        17. Massi F, Johnson E, Wang C, Rance M, Palmer AG. NMR R1 rho rotating-frame relaxation with weak radio frequency fields. J Am Chem Soc. 2004 Feb 25; 126(7):2247-56.
          View in: PubMed
        18. Massi F, Palmer AG. Temperature dependence of NMR order parameters and protein dynamics. J Am Chem Soc. 2003 Sep 17; 125(37):11158-9.
          View in: PubMed
        19. Massi F, Straub JE. Structural and dynamical analysis of the hydration of the Alzheimer's beta-amyloid peptide. J Comput Chem. 2003 Jan 30; 24(2):143-53.
          View in: PubMed
        20. Massi F, Klimov D, Thirumalai D, Straub JE. Charge states rather than propensity for beta-structure determine enhanced fibrillogenesis in wild-type Alzheimer's beta-amyloid peptide compared to E22Q Dutch mutant. Protein Sci. 2002 Jul; 11(7):1639-47.
          View in: PubMed
        21. Massi F, Straub JE. Probing the origins of increased activity of the E22Q "Dutch" mutant Alzheimer's beta-amyloid peptide. Biophys J. 2001 Aug; 81(2):697-709.
          View in: PubMed
        22. Massi F, Straub JE. Energy landscape theory for Alzheimer's amyloid beta-peptide fibril elongation. Proteins. 2001 Feb 1; 42(2):217-29.
          View in: PubMed
        23. Massi F, Peng JW, Lee JP, Straub JE. Simulation study of the structure and dynamics of the Alzheimer's amyloid peptide congener in solution. Biophys J. 2001 Jan; 80(1):31-44.
          View in: PubMed
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