Professor Andrew Miranker

 Yale University, USA

 http://miranker.sites.yale.edu/andrew-miranker

The “central dogma” is a phrase coined in 1958 by Francis Crick to describe the universal observation that DNA codes for RNA which codes for proteins.  Implicit in this description is the tenet that a linear chain of amino acids represents a complete code for a molecular structure.  The study of protein folding is predicated on two observations.  First, the functional structure of a protein resides at the free energy minimum of all possible conformations.  Second, that despite an astronomical number of possible configurations, proteins successfully and independently adopt the functional one in a finite amount of time. 

Research in the Miranker lab focuses on the energetic and structural limits of these basic assertions by studying their violations.  This includes interests in kinetically as opposed to thermodynamically stabilized states.  Furthermore, we are interested in proteins which are intrinsically unfolded.  Such systems become structured and functional only upon binding a partner, such as another protein or lipid bilayer.  Finally, for a number of diseases, such as Alzheimer’s and type II diabetes, the pathology includes proteins that appear to aggregate into a form more stable than their functional precursors. 

That normally soluble proteins are capable of aggregating is a well known frustration.  Careful analysis, however,  reveals that in many instances of disease, the aggregates are actually highly structured.  These aggregates are typically called amyloid fibers and are defined by the presence of a central core of β-strands stacked at right angles to the long axis of the fiber.  The initial formation of such structures is a rare event.  However, once present, fibers template and appear to catalyze their own formation.  The resultant structures are exceptionally resistant to degradation and disassembly by chemical or proteolytic means.  

The members of the Miranker Lab are guided by a combined fascination for both physical chemistry and molecular medicine.  As a result, we study systems which serve not only as general models of amyloid formation, but also directly affect our understanding of human pathophysiology.  Projects currently underway are therefore focused on model peptides, islet amyloid polypeptide from type II diabetes, and b2 microglobulin which forms amyloid deposits in renal failure patients on dialysis therapy.  Our approaches are kinetic, thermodynamic and structural in scope, enabling our investigations to be conducted at a molecular level.  In general, this includes but is not limited to the use optical spectroscopies, NMR, X-ray crystallography and hydrogen exchange mass spectrometry.