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Heinrich Roder, PhD
About
Professor
Head and Neck Cancer TRDG Member
Professor, Department of Biochemistry, Temple University
Adjunct Professor, Department of Biochemistry and Biophysics, University of Pennsylvania
Research Program
Education and Training
Educational Background
- PhD, Biophysics, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland, 1981
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
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.
Lab Staff
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
Contact Information
Heinrich.Roder@fccc.edu
Office Phone: 215-728-3123
Fax: 215-728-3574
Office: R414
Lab: R407
Lab Phone: 215-728-3151
Professor
Head and Neck Cancer TRDG Member
Professor, Department of Biochemistry, Temple University
Adjunct Professor, Department of Biochemistry and Biophysics, University of Pennsylvania
Research Program
Education
Educational Background
- PhD, Biophysics, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland, 1981
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 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
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.
Lab Staff
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
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