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Francesca Massi PhD

TitleAssociate Professor
InstitutionUMass Chan Medical School
DepartmentBiochemistry and Molecular Biotechnology
AddressUMass Chan Medical School
364 Plantation Street LRB
Worcester MA 01605
Phone508-856-4501
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentBiochemistry and Molecular Biotechnology

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentBiochemistry and Molecular Pharmacology

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentBioinformatics and Computational Biology

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentPostbaccalaureate Research Education Program

    InstitutionUMass Chan Programs, Centers and Institutes
    DepartmentBioinformatics and Integrative Biology


    Collapse Biography 
    Collapse education and training
    Boston University, Boston, MA, United StatesMAChemistry
    Boston University, Boston, MA, United StatesPHDChemistry

    Collapse Overview 
    Collapse overview


    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.


    Collapse 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.



    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    Newest   |   Oldest   |   Most Cited   |   Most Discussed   |   Timeline   |   Field Summary   |   Plain Text
    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Morgan BR, Massi F. The Role of Substrate Mediated Allostery in the Catalytic Competency of the Bacterial Oligosaccharyltransferase PglB. Front Mol Biosci. 2021; 8:740904. PMID: 34604309.
      Citations:    
    2. Schmidt EJ, Funes S, McKeon JE, Morgan BR, Boopathy S, O'Connor LC, Bilsel O, Massi F, J├ęgou A, Bosco DA. ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization. Proc Natl Acad Sci U S A. 2021 06 08; 118(23). PMID: 34074767.
      Citations: 2     Fields:    Translation:HumansAnimalsCells
    3. Ryder SP, Morgan BR, Coskun P, Antkowiak K, Massi F. Analysis of Emerging Variants in Structured Regions of the SARS-CoV-2 Genome. Evol Bioinform Online. 2021; 17:11769343211014167. PMID: 34017166.
      Citations:    
    4. Ryder SP, Morgan BR, Massi F. Analysis of Rapidly Emerging Variants in Structured Regions of the SARS-CoV-2 Genome. bioRxiv. 2020 Jun 30. PMID: 32577650.
      Citations:    
    5. Tavella D, Ertekin A, Schaal H, Ryder SP, Massi F. A Disorder-to-Order Transition Mediates RNA Binding of the Caenorhabditis elegans Protein MEX-5. Biophys J. 2020 04 21; 118(8):2001-2014. PMID: 32294479.
      Citations: 2     Fields:    Translation:AnimalsCells
    6. Basak S, Nobrega RP, Tavella D, Deveau LM, Koga N, Tatsumi-Koga R, Baker D, Massi F, Matthews CR. Networks of electrostatic and hydrophobic interactions modulate the complex folding free energy surface of a designed ?? protein. Proc Natl Acad Sci U S A. 2019 04 02; 116(14):6806-6811. PMID: 30877249.
      Citations: 7     Fields:    Translation:Cells
    7. Tavella D, Zitzewitz JA, Massi F. Characterization of TDP-43 RRM2 Partially Folded States and Their Significance to ALS Pathogenesis. Biophys J. 2018 11 06; 115(9):1673-1680. PMID: 30309612.
      Citations: 7     Fields:    Translation:HumansCells
    8. Massi F, Peng JW. Characterizing Protein Dynamics with NMR R 1? Relaxation Experiments. Methods Mol Biol. 2018; 1688:205-221. PMID: 29151211.
      Citations: 2     Fields:    Translation:Cells
    9. Morgan BR, Zitzewitz JA, Massi F. Structural Rearrangement upon Fragmentation of the Stability Core of the ALS-Linked Protein TDP-43. Biophys J. 2017 Aug 08; 113(3):540-549. PMID: 28793209.
      Citations: 1     Fields:    Translation:HumansCells
    10. Tavella D, Deveau LM, Whitfield TW, Massi F. Structural Basis of the Disorder in the Tandem Zinc Finger Domain of the RNA-Binding Protein Tristetraprolin. J Chem Theory Comput. 2016 Oct 11; 12(10):4717-4725. PMID: 27487322.
      Citations: 2     Fields:    Translation:HumansCells
    11. 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. PMID: 26551835.
      Citations: 6     Fields:    Translation:HumansCells
    12. 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):1503-1515. PMID: 25809263.
      Citations: 3     Fields:    Translation:HumansCells
    13. 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. PMID: 25356908.
      Citations: 7     Fields:    Translation:AnimalsCells
    14. 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. PMID: 25368328.
      Citations: 37     Fields:    Translation:HumansAnimalsCells
    15. Ertekin, A; Massi, F. eMagRes. Understanding the role of conformational dynamics in protein-ligand interactions using NMR relaxation methods. 2014; 3(3):255-266. View Publication.
    16. 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. PMID: 24935936.
      Citations: 29     Fields:    Translation:AnimalsCells
    17. 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. PMID: 23333740.
      Citations: 8     Fields:    Translation:Cells
    18. 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. PMID: 21507982.
      Citations: 22     Fields:    Translation:HumansCells
    19. Stewart MD, Morgan B, Massi F, Igumenova TI. Probing the determinants of diacylglycerol binding affinity in the C1B domain of protein kinase C?. J Mol Biol. 2011 May 20; 408(5):949-70. PMID: 21419781.
      Citations: 19     Fields:    Translation:AnimalsCells
    20. Morgan BR, Massi F. Accurate Estimates of Free Energy Changes in Charge Mutations. J Chem Theory Comput. 2010 Jun 08; 6(6):1884-93. PMID: 26615847.
      Citations: 8     Fields:    
    21. 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. PMID: 20506496.
      Citations: 7     Fields:    Translation:HumansAnimalsCells
    22. Ryder SP, Massi F. Insights into the structural basis of RNA recognition by STAR domain proteins. Adv Exp Med Biol. 2010; 693:37-53. PMID: 21189684.
      Citations: 6     Fields:    Translation:HumansAnimalsCells
    23. 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. PMID: 17353973.
      Citations: 3     Fields:    
    24. 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. PMID: 16953564.
      Citations: 42     Fields:    Translation:AnimalsCells
    25. 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. PMID: 16683750.
      Citations: 161     Fields:    Translation:Cells
    26. 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. PMID: 15722448.
      Citations: 51     Fields:    Translation:Cells
    27. 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. PMID: 14971961.
      Citations: 67     Fields:    Translation:Animals
    28. Massi F, Palmer AG. Temperature dependence of NMR order parameters and protein dynamics. J Am Chem Soc. 2003 Sep 17; 125(37):11158-9. PMID: 16220912.
      Citations: 17     Fields:    Translation:Cells
    29. 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. PMID: 12497595.
      Citations: 8     Fields:    Translation:Cells
    30. 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. PMID: 12070316.
      Citations: 31     Fields:    Translation:Cells
    31. 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. PMID: 11463618.
      Citations: 20     Fields:    Translation:HumansCells
    32. Massi F, Straub JE. Energy landscape theory for Alzheimer's amyloid beta-peptide fibril elongation. Proteins. 2001 Feb 01; 42(2):217-29. PMID: 11119646.
      Citations: 40     Fields:    Translation:HumansCells
    33. 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. PMID: 11159381.
      Citations: 43     Fields:    Translation:HumansCells
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