Section: Research

Francesca Massi, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Biochemistry and Molecular Pharmacology

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.  Scapharca dimeric hemoglobin (HbI)
Hemoglobin from Scapharca inaequivalvis is 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.

Office: LRB 925
Phone: 508-856-4501
E-mail: Francesca.Massi@umassmed.edu
Keywords: Protein Folding, Biophysics, Structural Biology, Biochemistry

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