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    Francesca Massi PhD

    TitleAssistant 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 - 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

        Francesca Massi

        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 the relationship between structure, stability, and dynamics of proteins. The fundamental phenomena that we investigate are:

        • The role of enzyme dynamics in catalysis.
        • The contribution of conformational dynamics to molecular recognition in proteins.
        • Protein aggregation in amyloidosis.

        We study these phenomena by solution nuclear magnetic resonance (NMR) spectroscopy and by computational methods. NMR spectroscopy is a powerful technique that can monitor protein motions over a broad range of time scales with atomic resolution. Computer simulations offer additional insight into the details of protein structure and dynamics in solution.

        Specific targets of our research program:

        1. Orotidine 5-monophosphate decarboxylase (ODCase).
        ODCase catalyzes the decarboxylation of orotidine 5’-monophosphate (OMP) to uridine 5’-monophosphate (UMP). This reaction is the last step in the de novo synthesis of pyrimidine nucleotides. Among protein catalysts that do not use metal ions or other cofactors, ODCase is the most proficient enzyme identified to date, and it enhances the uncatalyzed reaction rate by a factor of 1017. The detailed reaction mechanism of ODCase is still unknown. The enzyme undergoes a significant conformational change upon ligand binding, from an “open” state to a “closed” catalytically active state. We monitor the protein motions promoted by the binding of the ligand in order to understand the details of their essential role in the catalysis, and to elucidate the catalytic mechanism.


        2. b 2-microglobulin (b 2m)
        A number of human diseases originate from the deposition of stable, ordered protein aggregates called amyloid fibrils. Approximately 20 different amyloidogenic proteins have been identified and associated with diseases. Each of these amyloidogenic proteins has a different native structure, but all of the diverse amyloid fibers are composed by b strands. b 2-microglobulin is a 12 kD protein that folds as a seven-stranded antiparallel b sandwich. As a consequence of its dissociation from the MHCI, b 2m is present in the plasma under physiological conditions. After prolonged hemodialysis, individuals with renal dysfunction show an anomalous increase of concentration of b 2m in the plasma, which can lead to pathogenic amyloid fibril formation. In order to understand what causes the aggregation of b 2-microglobulin into amyloid deposits, we are studying the relationship between conformational flexibility and aggregation.


        3. Scapharcadimeric hemoglobin (HbI)
        Hemoglobin from Scapharcainaequivalvisis a homodimer that cooperatively binds oxygen and carbon monoxide. The arrangement of monomers is different from that of mammalian hemoglobins, allowing the two heme groups to be in closer proximity and in more direct communication. Ligand binding produces only a moderate structural change. Our goal is to use NMR spectroscopy to understand how HbI achieves cooperative ligand binding.



        Rotation Projects

        Rotation Projects

        Rotation projects are available to understand:

        1. The effect of enzyme loop motions on catalysis.
        Ligand binding promotes a structural transition in ODCase between an open and a closed state. What are the kinetic and thermodynamic properties of this transition? We will perform NMR relaxation experiments to monitor enzyme motions on different time scales. These results will provide direct insight into the opening and closing transitions of the enzyme and will correlate these transitions with the microscopic rate of catalytic turnover.

        2. The relationship between flexibility and aggregation propensity in b2-microglobulin. The presence of conformational flexibility indicates the transition between two or more states, one of which might be an intermediate that drives the monomeric b2m to associate into insoluble aggregates. In order to fully explore the connection between dynamics and aggregation propensity, we will study the structure and dynamics of the wild type b2m and different mutants that show different aggregation properties relative to the wild type protein.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. 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
        2. 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
        3. 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
        4. 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
        5. 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
        6. 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
        7. 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
        8. 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
        9. 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
        10. 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
        11. 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
        12. 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
        13. 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
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