Ronald Wetzel
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Phone (412) 383-5271
Fax (412) 648-8998

University of Pittsburgh
2046 Biomedical Science Tower 3

 

Ronald Wetzel


Professor emeritus
Department of Structural Biology



Aggregate structure. The protein aggregates associated with Alzheimer's Disease, Huntington's Disease, and other diseases tend to be highly ordered structures possessing, so far as we can establish, the same degree of packing specificity normally found in globular proteins. We use standard techniques like CD, FTIR, and EM to study the gross morphology of these aggregates. We attempt to get at finer structural points by adapting other methods previously applied to globular proteins Fibril assembly and inhibition.
 
We are interested in fibril assembly mechanism, kinetics and thermodynamics. We have developed and optimized a number of assays for following fibril formation that we routinely use to assess the kinetics and thermodynamics of fibril formation and to screen for inhibitors, both in the Alzheimer's Ab system and in the Huntington's Disease polyglutamine system.
 
The basis of aggregate cytotoxicity. We are interested in the mechanisms by which cells die or become dystrophic in response to aggregates. The mechanism we are particularly interested in has been called the "recruitment" or "sequestration" mechanism. We are studying polyglutamine aggregation in vitro to develop the biophysical underpinnings of this mechanism, and are also studying what happens when polyglutamine aggregates made in vitro are introduced into cells.

Visit Ron's lab website


Education & Training

Undergraduate
Drexel University, Philadelphia
B.S. 1969 in Chemistry

Postgraduate
Max Planck Institute
Goettingen, German 1973 - 1975

Yale University
New Haven 1975 - 1978



Awards & Honors


1998    Zenith Award, Alzheimer's Association 
1999    Lieberman Award, Hereditary Disease Foundation



Representative Publications


Mishra, R., Jayaraman, M., Roland, B.P., Landrum, E., Fullam, T., Kodali, R., Thakur, A.K., Arduini, I., & Wetzel, R., Inhibiting nucleation of amyloid structure in a huntingtin fragment by targeting α-helix rich oligomeric intermediates.  J. Mol. Biol. 415: 900-917. 2012.

Jayaraman, M., Mishra, R., Kodali, R., Thakur, A.K., Koharudin, L.M.I., Gronenborn, A.M., & Wetzel, R., Kinetically competing huntingtin aggregation pathways control amyloid polymorphism and properties. Biochem. 51: 2706-2716. 2012.

Mishra, R., Hoop, C.L., Kodali, R., Sahoo, B., van der Wel, P.C.A., & Wetzel, R., Serine phosphorylation suppresses huntingtin amyloid accumulation by altering protein aggregation properties. J. Mol. Biol. 424:1-14. 2012.

Kar, K., Hoop, C.L., Drombosky, K.W., Baker, M.A., Kodali, R., Arduini, I., van der Wel, P.C.A., Horne, W.S., & Wetzel, R., -hairpin-mediated nucleation of polyglutamine amyloid formation.  J. Mol. Biol., 425: 1183-1197. 2013.

Nafie, L.A., Kurouski, D. , Kar, K., Wetzel, R., Dukor, R.K., and Lednev, I.K., Levels of supramolecular chirality of polyglutamine aggregates revealed by vibrational circular dichroism. FEBS Letts.: 587: 1638-1643. 2013.


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Active Grants


Mechanisms of Amyloid Nucleation
04/01/12 – 03/31/17
National Institutes of Health
R01

Structures and Properties of Polyglutamine Proteins and Their Aggregates
06/15/01 – 05/31/16
National Institutes of Health
R01

Training in Molecular Biophysics and Structural Biology
07/01/11 – 06/30/16
National Institutes of Health
T32

 



Rieko Ishima
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Phone (412) 648-9056
Fax (412) 648-9008

University of Pittsburgh
1037 Biomedical Science Tower 3

 

Rieko Ishima

Associate Professor


The major objective of our research has been to determine protein structure and dynamics using nuclear magnetic resonance (NMR); spectroscopy, in order to elucidate protein function particularly relating to protein-ligand interactions.



Visit Ishima lab website


Education & Training

Graduate

Kyoto University, Kyoto, Japan
Ph.D., 1992 in Chemistry, Supervisor:  Dr. Kazuyuki Akasaka

Postgraduate

Ontario Cancer Institute
Postdoctoral Fellow 1995 – 1997


Representative Publications


Webb, C., Upadhyay, A., Giuntini, F., Eggleston, I., Furutani-Seiki, M., Ishima, R. & Bagby, S. (2011) Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway. Biochemistry, 50, 3300-9.

Myint, W., Cai, Y., Schiffer, C., Ishima, R. (2012) Quantitative comparison of errors in 15N transverse relaxation rates measured using various CPMG phasing schemes. J Biomol NMR, 53, 13-23.

Cai, Y., Yilmaz, N.K., Myint, W., Ishima, R., Schiffer, C. (2012) Differential Flap Dynamics in Wild-type and a Drug Resistant Variant of HIV-1 Protease Revealed by Molecular Dynamics and NMR Relaxation. J Chem Theory Comput. 8, 3452-62.

Liriano,  M.A., Varney, K.M., Wright, N.T., Hoffman, C.L.,  Toth, E.A., Ishima, R., and Weber, D.J. (2012) Target binding to S100B reduces dynamic properties and increases

Christen, M.T., Menon, L., Myshakina, N.A., Ahn, J., Parniak, M.A. & Ishima, R. (2012) Structural Basis of the Allosteric Inhibitor Interaction on the HIV-1 Reverse Transcriptase RNase H domain. Chemical Biology & Drug Design, 80, 706-16.



Active Grants


Conformational dynamics and inhibitor responses of HIV-1 RT RNase H in solution
10/01/13 – 08/31/17
National Institutes of Health
R01

Pittsburgh Center for HIV Protein Interactions (PCHPI)
09/30/12 – 07/31/17
National Institutes of Health
P50

 

 

 



Peijun Zhang
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Phone (412) 383-5907
Fax (412) 648-9008

University of Pittsburgh
2050 Biomedical Science Tower 3

 

Peijun Zhang

Associate Professor


We are interested in structural and functional characterization of macromolecular assemblies using three-dimensional cryo-electron microscopy (cryoEM) and biochemical, biophysical methods. Proteins carry out their cellular functions through formation of dynamic multi-protein complexes and macromolecular assemblies. These complexes or machines are usually too large and/or too heterogeneous for structural solution by X-ray crystallography or NMR spectroscopy methods. CryoEM is uniquely poised for structure determination of large complexes and macromolecular assemblies, and their conformational changes to provide structural snapshots along dynamic processes. Our interest is to combine structural information obtained through cryoEM methods, with biochemical, physiological analysis to understand molecular mechanisms of protein complexes and machines. We currently focus on three research areas: (I) Understanding HIV-1 and host cell interactions during the early stages of virus infection; (II) Eliciting 3D architectures of the chemotaxis receptor signaling complexes and their assemblies to understand the molecular mechanism of signal transduction in bacterial chemotaxis; and (III) Technology development to enhance the capability of cryo-electron tomography for 3D architectures of native mammalian cells at different signaling state.


Visit Peijun's lab website


Education & Training

Undergraduate
Nanjing University, Nanjing, China
B.S., 1987 in Electrical Engineering

Graduate
Nanjing University, Nanjing, China
M.S., 1990 in Solid State Physics

University of Virginia
Ph.D., Physiology and Biophysics

Postgraduate
National Institute for Diabetes and Digestive and Kidney Diseases, NIH
Visiting Fellow 1998 – 2000, Program Director:  Dr. Hinshaw

National Cancer Institute, NIH
Postdoctoral Fellow 2000 – 2002, Program Director:  Dr. Subramanian



Awards & Honors


1999    Philips Best in Show Award, Chesapeake Society for Microscopy
2003    United States Department of Health and Human Services “On-the-Spot Award”
2005    Leica Best General Microscopy Presentation, Chesapeake Society for Microscopy
2007    Senior Vice Chancellor’s Award, University of Pittsburgh
2010    Travel award at the “Recent Advances and Future Prospects for Visualizing Macromolecular Complexes and Cellular Structures Workshop”


Representative Publications


Yang Y., Bhatti A., Ke D., Gonzalez-Juarrero M., Lenaerts A., Kremer L., Guerardel Y., Zhang P. and Ojhaa A. K.(2013) Exposure to a cutinase-like serine esterase triggers rapid lysis of multiple mycobacterial species. J. Biol. Chem. 288(1):382-92.

Gao X., Huang Y., Makhov A., Epperly M, Lu J., Grab S., Zhang P., Rohan L., Xie X., Wipf P., Greenberger J. and Li S. (2013) Nano-assembly of Surfactants with Interfacial Drug-Interactive Motifs as Tailor-Designed Drug Carriers. Mol. Pharmaceut.10(1):187-98.

Zhao G, Perilla J. R., Yufenyuy E. L., Meng X., Chen B., Ning J., Ahn J., Gronenborn A. M., Schulten K., Aiken C. and Zhang P. (2013). Structure of the Mature HIV-1 Capsid by Cryo-EM and All-Atom Molecular Dynamics Simulation. Nature 497, 643-646

Hickey R. J., Meng X., Zhang P. and Park S. (2013) Low-dimensional Nanoparticle Clustering in Polymer Micelles and Their Transverse Relaxivity Rates. ACS Nano 7(7):5824-33.

Zhang P., Huang Y., Makhov A.M., Gao X., Zhang P. and Li S. (2013). Characterization of Spherulites as a Lipidic Carrier for Low and High Molecular Weight Agents. Pharm Res. 30(6):1525-35. PMCID: 3654020



Active Grants


University of Pittsburgh Center for HIV Protein Interactions (PCHPI)
08/27/07 – 07/31/17
National Institutes of Health
P50

Structure and Function of Membrane Receptor Signaling Complex in Bacterial Chemotaxis
08/01/12 – 07/31/15
National Institutes of Health
R01





 


Patrick van der Wel
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Phone (412) 383-9896
Fax (412) 648-9008

University of Pittsburgh
2044 Biomedical Science Tower 3

 

Patrick van der Wel


Associate Professor


The Van der Wel group uses solid state NMR (ssNMR) spectroscopy and other experiments to study protein aggregation and protein-lipid interactions. With our structural studies we provide new insights into the molecular mechanisms that cause disease, with the aim of helping the development of treatments that target disease causes rather than symptoms. Using advanced magic angle spinning (MAS) ssNMR, we elucidate the protein misfolding and aggregation that underlies Huntington’s Disease and other protein deposition disorders. We also use ssNMR to study the structure of membrane-associated proteins, and the membranes to which they are bound. We are studying mitochondrial protein-lipid interactions that play a pivotal role in mitochondrial dysfunction and apoptosis, and thus are implicated in diseases ranging from cancer to neurodegenerative disease.


Visit Patrick's lab website


Education & Training

Undergraduate
Utrecht University, Utrecht, the Netherlands
B.S., 1996 in Chemistry

Graduate
University of Arkansas, Fayetteville, AR
Ph.D., 2002 in Biochemistry, Advisor:  Prof. Roger E. Koeppe II

Postgraduate
Massachusetts Institute of Technology, Cambridge, MA
Postdoctoral Fellow 2003 – 2008 in Biochemistry and solid-state NMR, Advisor:  Prof. Robert G. Griffin



Awards & Honors


2013    Eastern Analytical Symposium (EAS) New Faculty Award in NMR Spectroscopy


Representative Publications


Sivanandam, V.N, Jayaraman, M., Hoop, C.L., Kodali, R., Wetzel, R., and Van der Wel, P.C.A. The aggregation-enhancing Huntingtin N-terminus is helical in amyloid fibrils. J. Am. Chem. Soc. 2011; 133(12): 4558–4566

Li, J., Hoop, C.L., Kodali, R., Sivanandam, V.N., and Van der Wel, P.C.A. Amyloid-like fibrils from a domain-swapping protein feature a parallel, in-register conformation without native-like interactions. J. Biol Chem. 2011; 286(33):28988-28995

Hoop, C.L.; Sivanandam, V.N., Kodali, R., Srnec, M.N., and Van der Wel, P.C.A. Structural Characterization of the Caveolin Scaffolding Domain in Association with Cholesterol-Rich Membranes. Biochemistry. 2012; 51(1):90-99.

Kar, K., Arduini, I., Drombosky, K. W., Van der Wel, P. C. A.#, and Wetzel, R. # D-polyglutamine amyloid recruits L-polyglutamine monomers and kills cells. J Mol Biol 2014; 426(4): 816–29.

Hoop, C., Lin, H.-K.; Kar, K.; Hou, Z., Poirier, M., Wetzel, R., and Van der Wel, P.C.A. Polyglutamine amyloid core boundaries and flanking domain dynamics in huntingtin fragment fibrils determined by solid-state NMR. Biochemistry 2014; 53: 6653–6666.

Mandal, A., Hoop, C.L., DeLucia, M., Kodali, R., Kagan, V., Ahn, J., and Van der Wel, P.C.A. Structural changes and pro-apoptotic peroxidase activity of cardiolipin-bound mitochondrial cytochrome c. Biophys J 2015; 109: 1873–1884

Hoop, C.L., Lin, H.-K., Kar, K., Magyarfalvi, G., Lamley, J.M., Boatz, J.C., Mandal, A., Lewandowski, J.R., Wetzel, R., and Van der Wel, P.C.A. Huntingtin exon 1 fibrils feature an interdigitated beta-hairpin-based polyglutamine core. Proc Natl Acad Sci USA. 2016; 113(6): 1546-51

Merg, A.D., Boatz, J.C., Mandal, A., Zhao, G., Mokashi-Punekar, S., Liu, C., Wang, X., Zhang, P., Van der Wel, P.C.A., and Rosi, N.L. Peptide-directed assembly of single-helical gold nanoparticle superstructures exhibiting intense chiroptical activity. J Am Chem Soc. 2016; 138(41):13655-13663.

 



Active Grants


Structural Polymorphism in the Misfolding and Aggregation of Expanded Polyglutamine Proteins
01/01/15 – 12/31/19
National Institutes of Health
R01

The molecular basis of cardiolipin-protein interactions implicated in intrinsic apoptosis.
10/01/16 – 09/30/20
National Institutes of Health
R01