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Heinrich Roder, PhD

Heinrich Roder, PhD
About

Professor

Professor, Department of Biochemistry, Temple University

Adjunct Professor, Department of Biochemistry and Biophysics, University of Pennsylvania

Research Program

Structural changes in cytochrome c upon CO binding to the heme
Kinetics of loop formation in unfolded cytochrome c
Residues in staphylococcal nuclease targeted for Trp substitution
Capillary mixer for ultrafast quenched-flow H/D exchange experiments
Unfolding of WT apomyoglobin (left) and L115A mutant (right) at pH 4.0
Domain structure of NHERF1 and 3D structure of PDZ domains
Figure 7
Rapid formation of an intermediate during folding of the human prion protein
Conformational changes associated with zymogen activation of factor XI
10 / 10Dimeric A4 dimerization domain of factor FXI

 

Education, Training & Credentials

Educational Background

  • PhD, Biophysics, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland, 1981
  • MA, University of Pennsylvania, Philadelphia, PA, 1990

Memberships

  • Biophysical Society
  • American Association for the Advancement of Science
  • Protein Folding Consortium
  • Protein Society
  • American Chemical Society

Honors & Awards

  • Site Visit, NIH Bioengineering Science and Technology IRG, 2015
  • NSF Chemistry of Life Processes Panel, 2014
  • Keynote Speaker, NJACS, Princeton NJ, 2014
  • External Review Committee, Department of Biochemistry, University of Zurich, Switzerland, 2013
  • NIH NHLBI Board of Counselors, 2008
  • NIH Molecular Structure & Function B Study Section, 2008
  • Speaker and Session Chair, ACS National Meeting, Philadelphia, 2008
  • Speaker and Session Chair, Symposium on Protein Folding Dynamics, American Chemical Society National Meeting, Philadelphia, 2008
  • Editorial Board Member, Protein Engineering, Design & Selection (2004-present), Experimental Biology and Medicine (2006-present), Biophysical Journal (2007-2012)
  • Speaker and Organizer, Plenary Closing Session, 17th Symposium of the Protein Society, Boston, 2003
  • Kresge Challenge Grant and Endowment Award, 1995
  • MA, Honoris causa, University of Pennsylvania, PA, 1990
Research Profile

Research Program

Research Interests

Protein folding, structure and function

  • Mechanisms of protein folding, focusing on fast kinetics and early structural events
  • Protein structure, dynamics and ligand interactions, focusing on signaling adapters
  • Functional roles of intrinsically disordered protein regions
  • Methods used include NMR spectroscopy, H/D exchange, fluorescence and rapid mixing

Lab Overview

Heinrich Roder Lab
 

A central theme of our research concerns the early stages of protein folding, which are critical for understanding how the native structure of a protein, and ultimately its function, are encoded in the amino acid sequence. The insight gained not only provides a basis for protein structure prediction and de novo design, but also contributes to our mechanistic understanding and treatment of a wide range of diseases that involve aggregation of denatured or misfolded proteins. The stability and folding dynamics of proteins also have major implications with respect to understanding of the physiological consequences of mutations, in vivo folding and other cellular processes, such as trafficking and degradation. We study the dynamics of protein folding on a microsecond time scale by coupling advanced mixing techniques with various detection methods, including fluorescence and H/D exchange labeling experiments with NMR detection. In combination with protein engineering, these approaches have provided detailed insight into the folding mechanisms of a diverse set of proteins [reviewed in Roder et al., 2006].  These approaches are currently being used to elucidate the sequence determinants for folding initiation and propagation of apomyoglobin, a prototypic alpha-helical protein, as well as other model proteins. Quenched-flow H/D exchange measurements, using a novel microfludic mixing device, allow us to detect the formation of individual hydrogen bonds in early folding intermediates populated within 100 μs of refolding. Recent results indicate that the initial compaction of cytochrome c involves specific formation of secondary and tertiary structure rather than a non-specific hydrophobic collapse [Fazelinia et al., 2014].

Our group also investigates the structure, dynamics and molecular interactions of various proteins of biomedical interest in solution by using NMR spectroscopy and other biophysical methods. A recent project is aimed at understanding the structural and dynamic properties of Na+/H+ exchanger regulatory factor (NHERF), a signaling protein comprising two PDZ domains and a C-terminal ezrin binding motif, as well as two long intrinsically disordered regions. Detailed NMR and thermodynamic studies have shown that the activity of NHERF as a signaling adaptor at the membrane-cytoskeleton interface is regulated by a complex equilibrium between various open and closed conformations. Two distinct closed states of NHERF are stabilized either by specific interactions between the second PDZ domain and the C-terminus, or by non-specific interactions involving a 90-residue flexible linker. In contrast to other PDZ domains, which generally recognized C-terminal residues in an extended conformation, the initially unstructured ezrin binding region of NHERF becomes helical when bound to the PDZ domain. Our current efforts are directed at understanding the impact of structural dynamics and order-disorder transitions on the functional interactions of NHERF, as well as the role of NHERF in modulating the activity and endocytosis of the epidermal growth factor receptor.

People

Hong Cheng, PhD

Staff Scientist

Room: R089
215-728-2841

Takuya Mizukami, PhD

Postdoctoral Associate

Room: R407
215-214-1583

Ruzaliya Fazlieva, MS

Scientific Technician II

Room: R254
215-728-2851
 
Former Staff

Ming Xu

Software

Sphere: A server program for hydrogen exchange rate estimation

Publications

Selected Publications

Honda, R. P., Xu, M., Yamaguchi, K., Roder, H., and Kuwata, K. (2015) A Native-like Intermediate Serves as a Branching Point between the Folding and Aggregation Pathways of the Mouse Prion Protein. Structure 2014; 23:1735-1742. PubMed

Fazelinia, H., Xu, M., Cheng, H., Roder, H. Ultrafast hydrogen exchange reveals specific structural events during the initial stages of folding of cytochrome c. J. Am. Chem. Soc. 2014; 136:733-740. PubMed

Montalvo, G. L., Gai, F., Roder, H., Degrado, W. F. Slow Folding-Unfolding Kinetics of an Octameric beta-Peptide Bundle. ACS Chem Biol. 2014; 9:276-81. PubMed

Mizukami, T., Xu, M., Cheng, H., Roder, H., Maki, K. Non-uniform chain collapse during early stages of staphylococcal nuclease folding by fluorescence resonance energy transfer and ultrarapid mixing methods. Protein Science 2013; 22:1336-48. PubMed

Xu M, Beresneva O, Rosario R, Roder H. Microsecond Folding Dynamics of Apomyoglobin at Acidic pH. J Phys Chem B. 2012; 116(23):7014-25. PubMed

Korendovych I V, Kulp DW, Wu Y, Cheng H, Roder H, DeGrado WF. Design of a switchable eliminase. Proc Natl Acad Sci U S A. 2011; 108:6823-7. PubMed

Chen KC, Xu M, Wedemeyer WJ, Roder H. Microsecond unfolding kinetics of sheep prion protein reveals an intermediate that correlates with susceptibility to classical scrapie. Biophys J. 2011;101:1221-30. PubMed

Lau WL, DeGrado WF, Roder H. The effects of pKa tuning on the thermodynamics and kinetics of folding: Design of a solvent-shielded carboxylate pair at the “a”position of a coiled coil. Biophys J. 2010; 99:2299-2308. PubMed

Cheng H, Li J, Fazlieva R, Dai Z, Bu Z, Roder H. Autoinhibitory interactions between the PDZ2 and C-terminal domains in the scaffolding protein NHERF1. Structure. 2009;17(5):660-669. PubMed

Latypov RF, Maki K, Cheng H, Luck SD, Roder H. Folding mechanism of reduced Cytochrome c: equilibrium and kinetic properties in the presence of carbon monoxide. J Mol Biol. 2008;383(2):437-53. PubMed

Additional Publications

My NCBI

This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
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