Mark Yeager
- Phone: 858-344-1834
Primary Appointment
Harrison Distinguished Professor, Molecular Physiology and Biological Physics
Education
- BS, Chemistry, Carnegie Mellon University
- Mphil, Molecular Biophysics, Yale University
- PhD, Molecular Biophysics, Yale University
- MD, Medicine, Yale University School of Medicine
Research Disciplines
Biophysics, Biotechnology, Cardiovascular Biology, Physiology, Structural Biology
Research Description
The ultimate goal of our studies is to gain a deeper understanding of the molecular basis for important human diseases such as sudden death, myocardial infarction, rotavirus infection and HIV infection that cause substantial mortality and suffering. The structural details revealed by our work may provide clues for the design of more effective and safer medicines.
At the basic science level, we are intrigued by biological questions at the interface between cell biology and structural biology. How do membrane channels open and close? How are signals transmitted across a cellular membrane when an extracellular ligand binds to a membrane receptor? How do viruses attach and enter host cells, replicate and assemble infectious particles?
In our laboratory we use high resolution electron cryo-microscopy (cryo-EM) and image processing to explore the molecular design of large, multicomponent supramolecular assemblies. Biological specimens are quick frozen in a physiological state to preserve their native structure and functional properties. A special advantage of this rapid-freezing method is that we can trap and image dynamic states of functioning macromolecular assemblies, such as open and closed states of membrane channels and viruses actively transcribing RNA. Three-dimensional density maps are obtained by digital image processing of the high-resolution electron micrographs. The rich detail in the maps reveals the structural organization of complex biological structures that can be related to the functional properties of such assemblies.
Research projects underway include the structure analysis of:
(1) Membrane proteins involved with cell-to-cell communication (gap junctions), water transport (aquaporins), ionic transport (potassium channels), transmembrane signaling (integrins), and viral recognition (rotavirus NSP4)
(2) RNA viruses responsible for significant human disease (rotavirus, astrovirus, retroviruses)
(3) RNA viruses used as model systems to understand mechanisms of pathogenesis (reovirus, nodaviruses, sobemoviruses, nudaurelia capensis omega Greek symbol virus, rice yellow mottle virus).
Clinical Research
Restenosis after Coronary Artery Angioplasty and Stent Placement:
Cardiovascular disease is the major cause of mortality in the United States. Most of these deaths are due to myocardial infarction caused by coronary artery atherosclerosis. A recent advancement in the treatment of coronary atherosclerosis is percutaneous transluminal coronary angioplasty combined with implantation of a balloon-expandable stent, which acts as a metallic scaffold to maintain patency of the diseased vessel. An adverse consequence of this procedure, which usually occurs within 3-12 months, is a proliferation of cells in the wall of the artery, a process termed neointimal hyperplasia. In many patients, neointimal hyperplasia narrows the lumen of the vessel (i.e. causes restenosis) and results in impaired myocardial blood flow. The porcine in vivo coronary artery injury model most closely resembles the process of restenosis after stent placement in humans and therefore provides the best system for delineating the pathophysiology of neointimal hyperplasia. Oligonucleotide microarray technology provides unprecedented opportunities to understand and treat human disease. The pattern of mRNA abundance can be used to gain insight into the “molecular circuitry” of disease. In collaboration with Dr. Robert Russo at Scripps Clinic , we are using this technology to explore the molecular basis of restenosis. Our preliminary analysis suggests that levels of mRNA for several genes are dramatically changed. Identification of cell receptors and signaling pathways associated with stent-induced vascular injury in this porcine model may guide the design of novel treatments to prevent restenosis in humans.
List of Publications in Pubmed
Personal Statement
At the basic science level, we are intrigued by biological questions at the interface between cell biology and structural biology. How do membrane channels open and close? How are signals transmitted across a cellular membrane when an extracellular ligand binds to a membrane receptor? How do viruses attach and enter host cells, replicate and assemble infectious particles?
In our laboratory we use high resolution electron cryo-microscopy (cryo-EM) and image processing to explore the molecular design of large, multicomponent supramolecular assemblies. Biological specimens are quick frozen in a physiological state to preserve their native structure and functional properties. A special advantage of this rapid-freezing method is that we can trap and image dynamic states of functioning macromolecular assemblies, such as open and closed states of membrane channels and viruses actively transcribing RNA. Three-dimensional density maps are obtained by digital image processing of the high-resolution electron micrographs. The rich detail in the maps reveals the structural organization of complex biological structures that can be related to the functional properties of such assemblies.
Research projects underway include the structure analysis of:
(1) Membrane proteins involved with cell-to-cell communication (gap junctions), water transport (aquaporins), ionic transport (potassium channels), transmembrane signaling (integrins), and viral recognition (rotavirus NSP4)
(2) RNA viruses responsible for significant human disease (rotavirus, astrovirus, retroviruses)
(3) RNA viruses used as model systems to understand mechanisms of pathogenesis (reovirus, nodaviruses, sobemoviruses, nudaurelia capensis omega Greek symbol virus, rice yellow mottle virus). Clinical Research
Restenosis after Coronary Artery Angioplasty and Stent Placement :
Cardiovascular disease is the major cause of mortality in the United States. Most of these deaths are due to myocardial infarction caused by coronary artery atherosclerosis. A recent advancement in the treatment of coronary atherosclerosis is percutaneous transluminal coronary angioplasty combined with implantation of a balloon-expandable stent, which acts as a metallic scaffold to maintain patency of the diseased vessel. An adverse consequence of this procedure, which usually occurs within 3-12 months, is a proliferation of cells in the wall of the artery, a process termed neointimal hyperplasia. In many patients, neointimal hyperplasia narrows the lumen of the vessel (i.e. causes restenosis) and results in impaired myocardial blood flow. The porcine in vivo coronary artery injury model most closely resembles the process of restenosis after stent placement in humans and therefore provides the best system for delineating the pathophysiology of neointimal hyperplasia. Oligonucleotide microarray technology provides unprecedented opportunities to understand and treat human disease. The pattern of mRNA abundance can be used to gain insight into the “molecular circuitry” of disease. In collaboration with Dr. Robert Russo at Scripps Clinic , we are using this technology to explore the molecular basis of restenosis. Our preliminary analysis suggests that levels of mRNA for several genes are dramatically changed. Identification of cell receptors and signaling pathways associated with stent-induced vascular injury in this porcine model may guide the design of novel treatments to prevent restenosis in humans.
Training
- Training in Cell and Molecular Biology
- Training in Molecular Biophysics
Selected Publications
2022
Pak, A. J., Gupta, M., Yeager, M., & Voth, G. A. (2022). Inositol Hexakisphosphate (IP6) Accelerates Immature HIV-1 Gag Protein Assembly toward Kinetically Trapped Morphologies. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 144(23), 10417-10428. doi:10.1021/jacs.2c02568
2021
Khan, A. K., Jagielnicki, M., Bennett, B. C., Purdy, M. D., & Yeager, M. (2021). Cryo-EM structure of an open conformation of a gap junction hemichannel in lipid bilayer nanodiscs. STRUCTURE, 29(9), 1040-+. doi:10.1016/j.str.2021.05.010
Narahari, A. K., Kreutzberger, A. J. B., Gaete, P. S., Chiu, Y. -H., Leonhardt, S. A., Medina, C. B., . . . Bayliss, D. A. (2021). ATP and large signaling metabolites flux through caspase-activated Pannexin 1 channels. ELIFE, 10. doi:10.7554/eLife.64787
Pak, A. J., Purdy, M. D., Yeager, M., & Voth, G. A. (2021). Preservation of HIV-1 Gag Helical Bundle Symmetry by Bevirimat Is Central to Maturation Inhibition. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 143(45), 19137-19148. doi:10.1021/jacs.1c08922
2020
Khan, A. K., Jagielnicki, M., McIntire, W. E., Purdy, M. D., Dharmarajan, V., Griffin, P. R., & Yeager, M. (2020). A Steric "Ball-and-Chain" Mechanism for pH-Mediated Regulation of Gap Junction Channels. CELL REPORTS, 31(3). doi:10.1016/j.celrep.2020.03.046
Mukherjee, S., Erramilli, S. K., Ammirati, M., Alvarez, F. J. D., Fennell, K. F., Purdy, M. D., . . . Kossiakoff, A. A. (2020). Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins. NATURE COMMUNICATIONS, 11(1). doi:10.1038/s41467-020-15363-0
Daniels, M. J., Jagielnicki, M., & Yeager, M. (2020). Structure/Function Analysis of human ZnT8 (SLC30A8): A Diabetes Risk Factor and Zinc Transporter. CURRENT RESEARCH IN STRUCTURAL BIOLOGY, 2, 144-155. doi:10.1016/j.crstbi.2020.06.001
2019
Han, H., Schubert, H. L., McCullough, J., Monroe, N., Purdy, M. D., Yeager, M., . . . Hill, C. P. (2020). Structure of spastin bound to a glutamate-rich peptide implies a hand-over-hand mechanism of substrate translocation. JOURNAL OF BIOLOGICAL CHEMISTRY, 295(2), 435-443. doi:10.1074/jbc.AC119.009890
Marques, M. A., Purdy, M. D., & Yeager, M. (2019). CryoEM maps are full of potential. CURRENT OPINION IN STRUCTURAL BIOLOGY, 58, 214-223. doi:10.1016/j.sbi.2019.04.006
DeLalio, L. J., Billaud, M., Ruddiman, C. A., Johnstone, S. R., Butcher, J. T., Wolpe, A. G., . . . Isakson, B. E. (2019). Constitutive SRC-mediated phosphorylation of pannexin 1 at tyrosine 198 occurs at the plasma membrane. JOURNAL OF BIOLOGICAL CHEMISTRY, 294(17), 6940-6956. doi:10.1074/jbc.RA118.006982
Daniels, M. J., & Yeager, M. (2019). Phosphorylation of TIP3 Aquaporins during Phaseolus vulgaris Embryo Development. CELLS, 8(11). doi:10.3390/cells8111362
Yeager, M. (2019). Editorial overview: Biophysical and computational methods, part B. CURRENT OPINION IN STRUCTURAL BIOLOGY, 58, V-VI. doi:10.1016/j.sbi.2019.07.002
Van Houten, M., Yang, Y., Hauser, A., Glover, D. K., Gan, L. -M., Yeager, M., & Salerno, M. (2019). Adenosine stress CMR perfusion imaging of the temporal evolution of perfusion defects in a porcine model of progressive obstructive coronary artery occlusion. NMR IN BIOMEDICINE, 32(11). doi:10.1002/nbm.4136
2018
Voth, G. A., & Yeager, M. (2018). Editorial overview: COSB biophysical and computational methods. CURRENT OPINION IN STRUCTURAL BIOLOGY, 52, VI-VII. doi:10.1016/j.sbi.2018.11.011
Purdy, M. D., Shi, D., Chrustowicz, J., Hattne, J., Gonen, T., & Yeager, M. (2018). MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(52), 13258-13263. doi:10.1073/pnas.1806806115
2017
Lopez, D., Pan, J. A., Pollak, P. M., Clarke, S., Kramer, C. M., Yeager, M., & Salerno, M. (2017). Multiparametric CMR imaging of infarct remodeling in a percutaneous reperfused Yucatan mini-pig model. NMR IN BIOMEDICINE, 30(5). doi:10.1002/nbm.3693
Pak, A. J., Grime, J. M. A., Sengupta, P., Chen, A. K., Durumeric, A. E. P., Srivastava, A., . . . Voth, G. A. (2017). Immature HIV-1 lattice assembly dynamics are regulated by scaffolding from nucleic acid and the plasma membrane. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114(47), E10056-E10065. doi:10.1073/pnas.1706600114
Chiu, Y. -H., Jin, X., Medina, C. B., Leonhardt, S. A., Kiessling, V., Bennett, B. C., . . . Bayliss, D. A. (2017). A quantized mechanism for activation of pannexin channels. Nature Communications, 8. doi:10.1038/ncomms14324
2016
Bayro, M. J., Ganser-Pornillos, B. K., Zadrozny, K. K., Yeager, M., & Tycko, R. (2016). Helical Conformation in the CA-SP1 Junction of the Immature HIV-1 Lattice Determined from Solid-State NMR of Virus-like Particles. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 138(37), 12029-12032. doi:10.1021/jacs.6b07259
Keller, T. C. S., Butcher, J. T., Broseghini-Filho, G. B., Marziano, C., DeLalio, L. J., Rogers, S., . . . Isakson, B. E. (2016). Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbX). HYPERTENSION, 68(6), 1494-1503. doi:10.1161/HYPERTENSIONAHA.116.08171
Toh, Y., Harper, J., Dryden, K. A., Yeager, M., Arias, C. F., Mendez, E., & Tao, Y. J. (2016). Crystal Structure of the Human Astrovirus Capsid Protein. JOURNAL OF VIROLOGY, 90(20), 9008-9017. doi:10.1128/JVI.00694-16
Wagner, J. M., Zadrozny, K. K., Chrustowicz, J., Purdy, M. D., Yeager, M., Ganser-Pornillos, B. K., & Pornillos, O. (2016). Crystal structure of an HIV assembly and maturation switch. ELIFE, 5. doi:10.7554/eLife.17063
Li, Y. -L., Chandrasekaran, V., Carter, S. D., Woodward, C. L., Christensen, D. E., Dryden, K. A., . . . Sundquist, W. I. (2016). Primate TRIM5 proteins form hexagonal nets on HIV-1 capsids. ELIFE, 5. doi:10.7554/eLife.16269
Grime, J. M. A., Dama, J. F., Ganser-Pornillos, B. K., Woodward, C. L., Jensen, G. J., Yeager, M., & Voth, G. A. (2016). Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly. NATURE COMMUNICATIONS, 7. doi:10.1038/ncomms11568
Bennett, B. C., Purdy, M. D., Baker, K. A., Acharya, C., McIntire, W. E., Stevens, R. C., . . . Yeager, M. (2016). An electrostatic mechanism for Ca2+ -mediated regulation of gap junction channels. NATURE COMMUNICATIONS, 7. doi:10.1038/ncomms9770
2015
Domanska, M. K., Dunning, R. A., Dryden, K. A., Zawada, K. E., Yeager, M., & Kasson, P. M. (2015). Hemagglutinin Spatial Distribution Shifts in Response to Cholesterol in the Influenza Viral Envelope. BIOPHYSICAL JOURNAL, 109(9), 1917-1924. doi:10.1016/j.bpj.2015.09.014
2014
Purdy, M. D., Bennett, B. C., McIntire, W. E., Khan, A. K., Kasson, P. M., & Yeager, M. (2014). Function and dynamics of macromolecular complexes explored by integrative structural and computational biology. CURRENT OPINION IN STRUCTURAL BIOLOGY, 27, 138-148. doi:10.1016/j.sbi.2014.08.006
Bhattacharya, A., Alam, S. L., Fricke, T., Zadrozny, K., Sedzicki, J., Taylor, A. B., . . . Yeager, M. (2014). Structural basis of HIV-1 capsid recognition by PF74 and CPSF6. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(52), 18625-18630. doi:10.1073/pnas.1419945112
Purdy, M., & Yeager, M. (2014). Mechanism of Cx26-G45E Deafness Mutant Dysregulation Explored by Molecular Dynamics Simulations. BIOPHYSICAL JOURNAL, 106(2), 801A. doi:10.1016/j.bpj.2013.11.4391
Ruan, Q., Ganser-Pornillos, B. K., Skinner, J. P., Gayda, S., Yeager, M., & Tetin, S. Y. (2014). Characterization of HIV-1 Capsid with Fluorescence Spectroscopy and Microscopy. BIOPHYSICAL JOURNAL, 106(2), 63A. doi:10.1016/j.bpj.2013.11.427
Erdbruegger, U., Rudy, C. K., Etter, M. E., Dryden, K. A., Yeager, M., Klibanov, A. L., & Lannigan, J. (2014). Imaging Flow Cytometry Elucidates Limitations of Microparticle Analysis by Conventional Flow Cytometry. CYTOMETRY PART A, 85A(9), 756-770. doi:10.1002/cyto.a.22494
2013
Kennedy, D. P., McRobb, F. M., Leonhardt, S. A., Purdy, M., Figler, H., Marshall, M. A., . . . Yeager, M. (2014). The Second Extracellular Loop of the Adenosine A1 Receptor Mediates Activity of Allosteric Enhancers. MOLECULAR PHARMACOLOGY, 85(2), 301-309. doi:10.1124/mol.113.088682
Lee, S. C., Bennett, B. C., Hong, W. -X., Fu, Y., Baker, K. A., Marcoux, J., . . . Zhang, Q. (2013). Steroid-based facial amphiphiles for stabilization and crystallization of membrane proteins. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(13), E1203-E1211. doi:10.1073/pnas.1221442110
Bennett, B., Purdy, M., Baker, K., McIntire, W., Stevens, R., Zhang, Q., & Yeager, M. (2013). X-Ray Structure of the Cx26 Gap Junction Channel and Comparison with the Cryo-EM Structure of Cx43. BIOPHYSICAL JOURNAL, 104(2), 42A-43A. doi:10.1016/j.bpj.2012.11.272
Ganser-Pornillos, B. K., Pornillos, O., Chandrasekaran, V., Cheng, A., Sundquist, W. I., & Yeager, M. (2013). The HIV-1 Capsid: Assembly and Restriction by TRIM5α. BIOPHYSICAL JOURNAL, 104(2), 12A. doi:10.1016/j.bpj.2012.11.096
2012
Yeager, M., Dryden, K. A., & Ganser-Pornillos, B. K. (2013). Lipid monolayer and sparse matrix screening for growing two-dimensional crystals for electron crystallography: methods and examples.. Methods in molecular biology (Clifton, N.J.), 955, 527-537. doi:10.1007/978-1-62703-176-9_28
Neves, M. A. C., Yeager, M., & Abagyan, R. (2012). Unusual Arginine Formations in Protein Function and Assembly: Rings, Strings, and Stacks. JOURNAL OF PHYSICAL CHEMISTRY B, 116(23), 7006-7013. doi:10.1021/jp3009699
Kunicki, T. J., Williams, S. A., Nugent, D. J., & Yeager, M. (2012). Mean Platelet Volume and Integrin Alleles Correlate With Levels of Integrins αIIbβ3 and α2β1 in Acute Coronary Syndrome Patients and Normal Subjects. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 32(1), 147-U337. doi:10.1161/ATVBAHA.111.239392
Dryden, K. A., Tihova, M., Nowotny, N., Matsui, S. M., Mendez, E., & Yeager, M. (2012). Immature and Mature Human Astrovirus: Structure, Conformational Changes, and Similarities to Hepatitis E Virus. JOURNAL OF MOLECULAR BIOLOGY, 422(5), 650-658. doi:10.1016/j.jmb.2012.06.029
2011
Ganser-Pornillos, B. K., Yeager, M., & Pornillos, O. (2012). Assembly and Architecture of HIV. VIRAL MOLECULAR MACHINES, 726, 441-465. doi:10.1007/978-1-4614-0980-9_20
Yeager, M. (2011). Design of in Vitro Symmetric Complexes and Analysis by Hybrid Methods Reveal Mechanisms of HIV Capsid Assembly. JOURNAL OF MOLECULAR BIOLOGY, 410(4), 534-552. doi:10.1016/j.jmb.2011.04.073
Pornillos, O., Ganser-Pornillos, B. K., & Yeager, M. (2011). Atomic-level modelling of the HIV capsid. NATURE, 469(7330), 424-+. doi:10.1038/nature09640
Kunicki, T. J., Williams, S. A., Nugent, D. J., & Yeager, M. J. (2011). Mean Platelet Volume and Integrin Alleles Strongly Correlate with Increased Levels of Integrins αIIbβ3 and α2β1: Clinical Implications for Platelet Reactivity in Acute Coronary Syndome. BLOOD, 118(21), 18-19.
McIntire, W. E., Wang, D. B., Sherman, N., Shannon, J., Leonhardt, S., Yeager, M., . . . Garrison, J. C. (2011). Specific association of β4γ5 to adenosine A1 and A2A receptors determined by stable isotope labeling with heavy amino acids in cell culture and mass spectrometry. FASEB JOURNAL, 25.
2010
Ganser-Pornillos, B. K., Chandrasekaran, V., Pornillos, O., Sodroski, J. G., Sundquist, W. I., & Yeager, M. (2011). Hexagonal assembly of a restricting TRIM5α protein. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 108(2), 534-539. doi:10.1073/pnas.1013426108
Wang, D. B., Sherman, N. E., Shannon, J. D., Leonhardt, S. A., Mayeenuddin, L. H., Yeager, M., & McIntire, W. E. (2011). Binding of β4γ5 by Adenosine A1 and A2A Receptors Determined by Stable Isotope Labeling with Amino Acids in Cell Culture and Mass Spectrometry. BIOCHEMISTRY, 50(2), 207-220. doi:10.1021/bi101227y
Gastaminza, P., Dryden, K. A., Boyd, B., Wood, M. R., Law, M., Yeager, M., & Chisari, F. V. (2010). Ultrastructural and Biophysical Characterization of Hepatitis C Virus Particles Produced in Cell Culture. JOURNAL OF VIROLOGY, 84(21), 10999-11009. doi:10.1128/JVI.00526-10
Pornillos, O., Ganser-Pornillos, B. K., Banumathi, S., Hua, Y., & Yeager, M. (2010). Disulfide Bond Stabilization of the Hexameric Capsomer of Human Immunodeficiency Virus. JOURNAL OF MOLECULAR BIOLOGY, 401(5), 985-995. doi:10.1016/j.jmb.2010.06.042
Hong, W. -X., Baker, K. A., Ma, X., Stevens, R. C., Yeager, M., & Zhang, Q. (2010). Design, Synthesis, and Properties of Branch-Chained Maltoside Detergents for Stabilization and Crystallization of Integral Membrane Proteins: Human Connexin 26. LANGMUIR, 26(11), 8690-8696. doi:10.1021/la904893d
Katritch, V., Jaakola, V. -P., Lane, J. R., Lin, J., IJzerman, A. P., Yeager, M., . . . Abagyan, R. (2010). Structure-Based Discovery of Novel Chemotypes for Adenosine A2A Receptor Antagonists. JOURNAL OF MEDICINAL CHEMISTRY, 53(4), 1799-1809. doi:10.1021/jm901647p
Bennett, B. C., & Yeager, M. (2010). The Lighter Side of a Sweet Reaction. STRUCTURE, 18(6), 657-659. doi:10.1016/j.str.2010.05.006