Eric H. Lee
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Education
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B.S.
(2002) - Neurobiology, Physiology, and Behavior. University of California - Davis
Research
 The Titin Z1Z2-Telethonin Complex |
Titin
Z1Z2-Telethonin Complex Muscle fibers, through their so-called thick and thin filaments, contract and extend in doing their work. To render the fibers elastic and protect them from overstretching, the thick filaments are connected through a long and thin elastic protein, titin, to the base of the fibers. Titin, by far the longest protein in human cells, is a molecular bungee cord and, like such cord, must be affixed firmly to the base. How this is done was a mystery until crystallographers took the first atomic resolution image of the system: it turns out that two titins are spliced together at their ends like ropes. The splicing involves a third small protein, the titin-telethonin-titin system forming a U. The U apparently is thrown over a bollard-like cellular structure to hold the thick filaments much like boats are held by bollards and ropes at their mooring place. The crystallographers teamed up with computational biologists to investigate the mechanical strength of the titin - telethonin - titin cord by means of molecular dynamics simulations using NAMD. As reported recently, the cord has great mechanical strength due to an extended network of hydrogen bonds between beta-strands, common structural features in proteins, that in the present case form a sheet extending through all three proteins. This discovery explains how living cells can splice cellular proteins together through a system of hydrogen-bonded beta strands that extend through several proteins. Interestingly, such beta-strands were seen previously in cases of diseases like Alzheimers where the feature leads, however, to pathological assembly of proteins. What needs to be understood now is how the telethonin glue is applied only to the right spots in the cell and how the cells prevent telethonin from splicing together the wrong proteins. For more information visit our Z1Z2-telethonin web page. |
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Mechanical Proteins The living state of biological cells manifests itself through mechanical motion on many length scales. Behind this motion are processes that generate and transform mechanical forces of various types. As with other cell functions, the machinery for cellular mechanics involves proteins. Their flexible structures can be deformed and restored, and are often essential for handling, transforming, and using mechanical force. For instance, proteins of muscle and the extracellular matrix exhibit salient elasticity upon stretching, mechanosensory proteins transduce weak mechanical stimuli into electrical signals, and so-called regulatory proteins force DNA into loops controlling, thereby, gene expression. In a recent review, the structure-function relationship of four protein complexes with well defined and representative mechanical functions has been described. The first protein system reviewed is titin, a protein that confers passive elasticity on muscle. The second system reviewed is the elastic extracellular matrix protein fibronectin and its cellular receptor integrin. The third protein system covered are the proteins cadherin and ankyrin involved in the transduction apparatus of mechanical senses and hearing. The last system surveyed is the lac repressor, a protein which regulates gene expression by looping DNA. In each case, molecular dynamics simulations using NAMD provided insights into the physical mechanisms underlying the associated mechanical functions of living cells. (more on our mechanobiology web site). |
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Muscle Protein Elasticity Muscle fibers, in contracting and extending, generate tremendous force that needs to be buffered to protect muscle from damage. This role falls to the protein titin, with about 27,000 amino acids the longest protein in human cells. Titin functions as a molecular rubber band, but unlike uniform rubber bands, titin is made from over 300 different protein domains strung into a chain. While experiments have found that the individual domains of titin feature remarkable resilience against mechanical stretching, little is known about the elasticity of the overall titin chain. Crystallographers teamed up with computational biologists to investigate this elasticity, focusing on two adjacent titin domains. Molecular dynamics simulations using NAMD suggest, as reported recently, that the overall elasticity of the titin chain stems in part from a zigzag, i.e., accordion-like, motion: as titin is contracted and extended, energy is stored and released in the angular tilt of adjacent domains. More on this investigation can be found here. |
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Blood Clot Protein Elasticity Bleeding through physical injury is stopped in animals through the formation of blood clots. Such clots, actually arising often in blood vessels without injury, can rupture due to the blood's shear forces and obstruct upstream smaller vessels leading to life threatening stroke, pulmonary embolism, and heart attack. Hence, a blood clot must be both mechanically stable to stop bleeding, yet elastic enough to avoid rupture. Fibrin, the main component of a blood clot, possesses the stated mechanical properties in healthy individuals, but in pathological circumstances needs to be managed through medication. Unfortunately, preventive treatment of blood clots is still a black art since the molecular basis of fibrin elasticity is unknown. Clinicians at the Mayo Clinic teamed up with computational biologists at the University of Illinois to investigate this elasticity, focusing on the protein fibrinogen, the building block of fibrin. The clinical researchers stretched individual fibrinogen molecules measuring the force needed to extend the molecules. They found a characteristic force - extension relationship and its dependence on blood pH and calcium concentration, but they could not interpret the finding chemically, a prerequisite for improving blood clot chemical management. The clinical researchers joined forces with computational biologists who could reproduce the measured force - extension relationship in steered molecular dynamics using NAMD. The simulations starting from known crystallographic structures of fibrinogen offered a full, i.e., atom resolution, chemical picture of fibrinogen elasticity. As reported recently by the clinical and computational researchers the insight gained opens new avenues for blood clot treatment. For example, it was found that pH and calcium concentrations alter the stiffness of blood clots, thereby opening pharmacological avenues for controlling the incidence of pathological blood clots. More on this investigation can be found here. |
Publications
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Molecular
basis of fibrin clot elasticity.
Bernard Lim, Eric H. Lee, Marcos Sotomayor, and Klaus Schulten. Structure,
16: 449-459, 2008. Secondary and tertiary structure elasticity of titin Z1Z2 and a titin chain model. Eric H. Lee, Jen Hsin, Olga Mayans, and Klaus Schulten. Biophysical Journal, 93:1719-1735, 2007. Molecular mechanisms of cellular mechanics. Mu Gao, Marcos Sotomayor, Elizabeth Villa, Eric Lee, and Klaus Schulten. Physical Chemistry - Chemical Physics, 8:3692-3706, 2006. Mechanical
strength of the titin Z1Z2/telethonin complex.
Eric H. Lee, Mu Gao, Nikos Pinotsis, Matthias Wilmanns, and
Klaus Schulten. Structure, 14:497-509, 2006. Non-TCBG publications:Obesity in BSB Mice Is Correlated with Expression of Genes for Iron Hemeostasis and Leptin. P. Farahani, S. Chiu, C. Bowlus, D. Boffelli, E. Lee, J. Fisler, R. Kraus, and C. Warden. Obesity Research, 12:191-204 (2004). |
Presentations
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Molecular Basis of Fibrin Clot Elasticity. Eric H. Lee, Bernard
Lim, Marcos Sotomayor, and Klaus Schulten.
Platform lecture at the Biophysical Society Meeting, 2008. Long Beach,
CA |
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Secondary and Tertiary Structure Elasticity of Titin Z1Z2 and the Titin Chain. Eric H. Lee, Jen Hsin, Olga Mayans, and Klaus Schulten. Biophysical Society Meeting, 2007. Baltimore, MD |
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Mechanical Stablility of the Titin Z1Z2-Telethonin Complex. Eric H. Lee, Mu Gao, Matthias Wilmanns, and Klaus Schulten. Biophysical Society Meeting, 2006. Salt Lake City, UT |
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Molecular Modeling and Dynamics Studies of a GB1 F26A Protein Fibril. Eric H. Lee, Angela Gronenborn, and Klaus Schulten. Biophysical Society Meeting, 2005. Long Beach, CA |
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Research Experience:
Graduate Student - Theoretical and
Computational
Biophysics Group, University of Illinois at Urbana-Champaign.
Advisor: Klaus
J. Schulten (2003-).
Post Graduate
Researcher - Department of
Surgery,
University of California at Davis School of Medicine.
Advisor: Bruce
M. Wolfe (2002-2003).
Research Assistant -Rowe
Human Genetics Program, University of California at Davis.
Advisor: Craig
H. Warden (2001-2002).