High Performance Computation
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.
The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes.
Hebda JA, Miranker AD. The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes. Annual Review Of Biophysics 2009, 38:125-52.
Metal binding sheds light on mechanisms of amyloid assembly.
Calabrese MF, Miranker AD. Metal binding sheds light on mechanisms of amyloid assembly. Prion 2009, 3:1-4.
Full List of PubMed Publications
- Birol M, Kumar S, Rhoades E, Miranker AD: Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid. Nat Commun. 2018 Apr 3; 2018 Apr 3. PMID: 29615609
- Kumar S, Birol M, Miranker AD: Foldamer scaffolds suggest distinct structures are associated with alternative gains-of-function in a preamyloid toxin. Chem Commun (Camb). 2016 May 11; 2016 Apr 15. PMID: 27079937
- Kumar S, Birol M, Schlamadinger DE, Wojcik SP, Rhoades E, Miranker AD: Foldamer-mediated manipulation of a pre-amyloid toxin. Nat Commun. 2016 Apr 25; 2016 Apr 25. PMID: 27108700
- White EM, Miranker AD: A solenoid design for assessing determinants of parallel β-sheet registration. Protein Eng Des Sel. 2015 Dec; 2015 Oct 20. PMID: 26487712
- Witten J, Ruschak A, Poterba T, Jaramillo A, Miranker AD, Jaswal SS: Mapping Protein Conformational Landscapes under Strongly Native Conditions with Hydrogen Exchange Mass Spectrometry. J Phys Chem B. 2015 Aug 6; 2015 Jul 27. PMID: 26146955
- Nath A, Schlamadinger DE, Rhoades E, Miranker AD: Structure-Based Small Molecule Modulation of a Pre-Amyloid State: Pharmacological Enhancement of IAPP Membrane-Binding and Toxicity. Biochemistry. 2015 Jun 9; 2015 May 22. PMID: 25966003
- Kumar S, Schlamadinger DE, Brown MA, Dunn JM, Mercado B, Hebda JA, Saraogi I, Rhoades E, Hamilton AD, Miranker AD: Islet amyloid-induced cell death and bilayer integrity loss share a molecular origin targetable with oligopyridylamide-based α-helical mimetics. Chem Biol. 2015 Mar 19; 2015 Mar 5. PMID: 25754474
- Rubio MA, Schlamadinger DE, White EM, Miranker AD: Peptide amyloid surface display. Biochemistry. 2015 Feb 3; 2015 Jan 20. PMID: 25541905
- Schlamadinger DE, Miranker AD: Fiber-dependent and -independent toxicity of islet amyloid polypeptide. Biophys J. 2014 Dec 2; 2014 Dec 2. PMID: 25468335
- Hebda JA, Magzoub M, Miranker AD: Small molecule screening in context: lipid-catalyzed amyloid formation. Protein Sci. 2014 Oct; 2014 Jul 28. PMID: 25043951
- Kumar S, Brown MA, Nath A, Miranker AD: Folded small molecule manipulation of islet amyloid polypeptide. Chem Biol. 2014 Jun 19; 2014 Jun 12. PMID: 24930968
- Last NB, Schlamadinger DE, Miranker AD: A common landscape for membrane-active peptides. Protein Sci. 2013 Jul; 2013 Jun 11. PMID: 23649542
- Kumar S, Miranker AD: A foldamer approach to targeting membrane bound helical states of islet amyloid polypeptide. Chem Commun (Camb). 2013 May 25. PMID: 23579860
- Last NB, Miranker AD: Common mechanism unites membrane poration by amyloid and antimicrobial peptides. Proc Natl Acad Sci U S A. 2013 Apr 16; 2013 Apr 1. PMID: 23576726
- Magzoub M, Miranker AD: Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide. FASEB J. 2012 Mar; 2011 Dec 19. PMID: 22183778
- Nath A, Miranker AD, Rhoades E: A membrane-bound antiparallel dimer of rat islet amyloid polypeptide. Angew Chem Int Ed Engl. 2011 Nov 11; 2011 Sep 22. PMID: 21948544
- Last NB, Rhoades E, Miranker AD: Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity. Proc Natl Acad Sci U S A. 2011 Jun 7; 2011 May 23. PMID: 21606325
- Wolfe LS, Calabrese MF, Nath A, Blaho DV, Miranker AD, Xiong Y: Protein-induced photophysical changes to the amyloid indicator dye thioflavin T. Proc Natl Acad Sci U S A. 2010 Sep 28; 2010 Sep 8. PMID: 20826442
- Saraogi I, Hebda JA, Becerril J, Estroff LA, Miranker AD, Hamilton AD: Synthetic alpha-helix mimetics as agonists and antagonists of islet amyloid polypeptide aggregation. Angew Chem Int Ed Engl. 2010. PMID: 20029853
- Nath A, Trexler AJ, Koo P, Miranker AD, Atkins WM, Rhoades E: Single-molecule fluorescence spectroscopy using phospholipid bilayer nanodiscs. Methods Enzymol. 2010. PMID: 20580961
- Williamson JA, Loria JP, Miranker AD: Helix stabilization precedes aqueous and bilayer-catalyzed fiber formation in islet amyloid polypeptide. J Mol Biol. 2009 Oct 23; 2009 Jul 30. PMID: 19647750
- Ruschak AM, Miranker AD: The role of prefibrillar structures in the assembly of a peptide amyloid. J Mol Biol. 2009 Oct 16; 2009 Jun 12. PMID: 19524594
- Hebda JA, Saraogi I, Magzoub M, Hamilton AD, Miranker AD: A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes. Chem Biol. 2009 Sep 25. PMID: 19778722
- Blaho DV, Miranker AD: Delineating the conformational elements responsible for Cu(2+)-induced oligomerization of beta-2 microglobulin. Biochemistry. 2009 Jul 21. PMID: 19518133
- Hebda JA, Miranker AD: The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes. Annu Rev Biophys. 2009. PMID: 19416063
- Calabrese MF, Miranker AD: Metal binding sheds light on mechanisms of amyloid assembly. Prion. 2009 Jan-Mar; 2009 Jan 28. PMID: 19377278
- Knight JD, Williamson JA, Miranker AD: Interaction of membrane-bound islet amyloid polypeptide with soluble and crystalline insulin. Protein Sci. 2008 Oct; 2008 Sep 2. PMID: 18765820
- Calabrese MF, Eakin CM, Wang JM, Miranker AD: A regulatable switch mediates self-association in an immunoglobulin fold. Nat Struct Mol Biol. 2008 Sep. PMID: 19172750
- Koo BW, Hebda JA, Miranker AD: Amide inequivalence in the fibrillar assembly of islet amyloid polypeptide. Protein Eng Des Sel. 2008 Mar. PMID: 18299291
- Jaswal SS, Miranker AD: Scope and utility of hydrogen exchange as a tool for mapping landscapes. Protein Sci. 2007 Nov. PMID: 17962401
- Ruschak AM, Miranker AD: Fiber-dependent amyloid formation as catalysis of an existing reaction pathway. Proc Natl Acad Sci U S A. 2007 Jul 24; 2007 Jul 17. PMID: 17640888
- Calabrese MF, Miranker AD: Formation of a stable oligomer of beta-2 microglobulin requires only transient encounter with Cu(II). J Mol Biol. 2007 Mar 16; 2006 Dec 19. PMID: 17254602
- Williamson JA, Miranker AD: Direct detection of transient alpha-helical states in islet amyloid polypeptide. Protein Sci. 2007 Jan; 2006 Nov 22. PMID: 17123962
- Knight JD, Hebda JA, Miranker AD: Conserved and cooperative assembly of membrane-bound alpha-helical states of islet amyloid polypeptide. Biochemistry. 2006 Aug 8. PMID: 16878984
- Eakin CM, Berman AJ, Miranker AD: A native to amyloidogenic transition regulated by a backbone trigger. Nat Struct Mol Biol. 2006 Mar; 2006 Feb 19. PMID: 16491088
- Eakin CM, Miranker AD: From chance to frequent encounters: origins of beta2-microglobulin fibrillogenesis. Biochim Biophys Acta. 2005 Nov 10; 2005 Sep 22. PMID: 16226064
- Miranker AD: Quantitative measurement of fibrillogenesis by mass spectrometry. Methods Mol Biol. 2005. PMID: 15980602
- Koo BW, Miranker AD: Contribution of the intrinsic disulfide to the assembly mechanism of islet amyloid. Protein Sci. 2005 Jan; 2004 Dec 2. PMID: 15576552
- Knight JD, Miranker AD: Phospholipid catalysis of diabetic amyloid assembly. J Mol Biol. 2004 Aug 27. PMID: 15321714
- Eakin CM, Attenello FJ, Morgan CJ, Miranker AD: Oligomeric assembly of native-like precursors precedes amyloid formation by beta-2 microglobulin. Biochemistry. 2004 Jun 22. PMID: 15196023
- Miranker AD: Unzipping the mysteries of amyloid fiber formation. Proc Natl Acad Sci U S A. 2004 Mar 30; 2004 Mar 22. PMID: 15070716
- Larson JL, Miranker AD: The mechanism of insulin action on islet amyloid polypeptide fiber formation. J Mol Biol. 2004 Jan 2. PMID: 14659752
- Eakin CM, Knight JD, Morgan CJ, Gelfand MA, Miranker AD: Formation of a copper specific binding site in non-native states of beta-2-microglobulin. Biochemistry. 2002 Aug 27. PMID: 12186550
- Padrick SB, Miranker AD: Islet amyloid: phase partitioning and secondary nucleation are central to the mechanism of fibrillogenesis. Biochemistry. 2002 Apr 9. PMID: 11926832