Andrew D Miranker PhD

Professor of Molecular Biophysics and Biochemistry

Research Interests

Conformational changes in proteins which give rise to a special class of protein complex known as amyloid fibrils


Research Summary

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.
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 ?-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. 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.

Extensive Research Description

Research in our laboratory is focused on conformational changes in proteins which give rise to a special class of protein complex known as amyloid fibrils. This folding problem is particularly fascinating as proteins which are seemingly unrelated in primary sequence and in their native 3 dimensional structure form aggregates which share common structural features. Depending on the protein involved, fibril formation gives rise or contributes to the pathogenesis of more than 20 clinical conditions. Projects currently underway in the laboratory include the islet amyloid polypeptide system which forms fibrils in the pancreas of type II diabetics, and beta-2 microglobulin which forms deposits on the connective tissues of long term dialysis patients. We are studying both the folding and the fibrillogenesis properties of these systems. Biophysical techniques enable these investigations to be conducted at a molecular level. These include high field NMR, optical spectroscopy and electrospray ionization mass spectrometry.


Selected Publications

  • Hebda, JA and Miranker, AD (2009) The Interplay of Catalysis and Toxicity by Amyloid Intermediates on Lipid Bilayers: Insights from Type II Diabetes, Annual Reviews in Biophysics 38:125–152.
  • Calabrese, MF and Miranker, AD (2009) Metal binding sheds light on mechanisms of amyloid assembly, Prion 3:1-4.

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