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Elan Eisenmesser, Assistant Professor

Ph.D. (1998), Purdue University
 

 

 

Contact Info:

Molecular Biology
University of Colorado

Elan Eisenmesser, Ph.D.  Research One South
(RC1-South), Room 9117 Elan.Eisenmesser@ucdenver.edu Phone: 303-724-3246

We are interested in understanding multiple molecular interactions that go awry during both inflammatory diseases and cancer progression. The novelty in our group’s approach is that we utilize highly integrative methods to probe interactions from atomic resolution techniques to cell-based techniques. When cellular and clinical studies are combined with molecular and biochemical studies, a complete understanding of the particular system under study can be drawn. This will allow our lab to utilize both rational and irrational-based approaches to block many of the proteins upregulated during disease progression. Several of these projects are described herein.

Cyclophilins and enzyme dynamics:

Understanding the intimacy between structure, dynamics and function is critical for fully characterizing macromolecules, especially for enzymes that depend on rapid conformational changes for catalysis. Recently, similar conformational changes that occur within active enzymes have also been identified in the absence of substrates and thus, may allow important conformations to be dynamically sampled such as those that initiate substrate binding and catalysis. This suggests that like sequence and structure, inherent motions of enzymes that are associated with catalysis may also be an evolutionary trait. We are currently studying numerous members of the human cyclophilin family of enzymes to understand how the inherent dynamics within this family is correlated to their catalytic function. Cyclophilins are involved in everything from protein folding to signal transduction and the prototypical cyclophilin, cyclophilin-A (CypA), comprises nearly 0.5% of the cytosolic protein. Not surprisingly, cyclophilins are involved in multiple diseases that include cancer and CypA is utilized by multiple pathogens for infection. While there has been great therapeutic interest in targeting cyclophilins, structure-based approaches have proven difficult, likely due to the fact that these enzymes are highly dynamic. Thus, understanding the dynamics of these moving targets may help bridge rational-based therapeutic strategies.

Extracellular cyclophilins and disease:

Intracellular cyclophilins are involved in multiple signal transduction pathways, yet the role of extracellular cyclophilins has recently emerged as a major contributor to disease progression that includes multiple cancers and inflammatory disorders. Together with several labs that include Dr. Michael Bukrinsky (Department of Microbiology and Tropical Medicine The George Washington University), we are characterizing the particular cyclophilins released from different cancer cells (i.e. leukemic, pancreatic cancer, and melanoma) as well as the particular proteins secreted in response to extracellular cyclophilins.

The EMMPRIN receptor and cell signaling:

The cellular receptor EMMPRIN (Extracellular Matrix Metalloproteinase Inducer or EMMPRIN, also known as CD147) plays a central role in numerous diseases and has more recently become a marker for several cancers. EMMPRIN plays several roles during disease progression that includes the stimulation of matrix metalloproteinases (MMPs), which are responsible for tumor invasion, and stimulation of many pro-inflammatory cytokines, which further contribute to tumor growth. EMMPRIN-mediated activity is regulated by both ligand independent and ligand dependent mechanisms, yet little is known about the molecular details of either mechanism. Interestingly, the EMMPRIN ligands are the cyclophilin class of extracellular enzymes and suggest that there is a catalytic role in EMMPRIN/cyclophilin interactions that lead to intracellular signaling. Thus, our lab is interested in characterizing both the ligand-independent and ligand-dependent role of EMMPRIN signaling at both the molecular and cellular level. Biophysical experiments that include nuclear magnetic resonance have revealed the molecular details of EMMPRIN self-association and its interactions with its cyclophilin enzyme ligands. Cell-based assays that include stable EMMPRIN knockdowns as well as stable transfected cell lines will allow us to relate the molecular details to several signaling events. Thus, our lab is the first to begin probing EMMPRIN directly in solution as well as to understand the relationship between cyclophilin-mediated catalysis of EMMPRIN on the outside of the cell to intracellular signaling.

Extracellular EMMPRIN and disease:

EMMPRIN is a unique receptor in that it mediates its activity as a transmembrane protein but is also excised from the cellular membrane as a soluble protein and released in its full-length form by microvesicle shedding. Once again, we are using a combination of biophysical, biochemical and cell-based techniques to reveal the particular extracellular EMMPRIN forms released from cancer cells and present within bodily fluids such as peripheral blood.​​​​​​​

 

Eisenmesser EZ, Post CB “Insights into tyrosine phosphorylation control of protein-protein association from the NMR structure of a band 3 peptide inhibitor bound to glyceraldehyde-3-phosphate dehydrogenase” Biochemistry 37:867-77 (1998).

Post CB, Gaul BS, Eisenmesser EZ, Schneider ML “NMR structure of phospho-tyrosine signaling complexes” Med Res Rev 19:295-305 (1999).

Pomes R, Eisenmesser EZ, Post CB, Roux B “Calculating excess chemical potentials using dynamic simulations in the fourth dimension” J Chem Phys 111:3387-95 (1999)

Eisenmesser EZ, Kapust RB, Nawrocki JP, Mazzulla MJ, Pannell LK, Waugh DS, Byrd RA “Expression, purification, refolding, and characterization of recombinant human interleukin-13: utilization of intracellular processing” Protein Expr Purif 20:186-95 (2000).

Eisenmesser EZ, Zabell AP, Post CB “Accuracy of bound peptide structures determined by exchange transferred nuclear Overhauser data: a simulation study” J Biomol NMR 17:17-32 (2000).

Kingston RL, Fitzon-Ostendorp T, Eisenmesser EZ, Schatz GW, Vogt VM, Post CB, Rossmann MG “Structure and self-association of the Rous sarcoma virus capsid protein” Structure 8:617-28 (2000).

Eisenmesser EZ, Horita DA, Altieri AS, Byrd RA “Solution structure of interleukin-13 and insights into receptor engagement” J Mol Biol. 310:231-41 (2001).

Eisenmesser EZ, Horita DA, Byrd RA “Secondary structure and backbone resonance assignments for human interleukin-13” J Biomol NMR 19:93-4 (2001).

Bosco DA, Eisenmesser EZ, Pochapsky S, Sundquist WI, Kern D “Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A” Proc Natl Acad Sci U S A. 99:5247-52 (2002).

Eisenmesser EZ, Bosco DA, Akke M, Kern D “Enzyme dynamics during catalysis” Science 295:1520-3 (2002).

Wolf-Watz M, Thai V, Henzler-Wildman K, Hadjipavlou G, Eisenmesser EZ, Kern D “Linkage between dynamics and catalysis in a thermophilic-mesophilic enzyme pair” Nat Struct Mol Biol. 11:945-9 (2004).

Eisenmesser EZ, Millet O, Labeikovsky W, Korzhnev DM, Wolf-Watz M, Bosco DA, Skalicky JJ, Kay LE, Kern D “Intrinsic dynamics of an enzyme underlies catalysis” Nature 438:117-21 (2005)

Kern D, Eisenmesser EZ, Wolf-Watz M “Enzyme dynamics during catalysis measured by NMR spectroscopy” Methods Enzymol. 394:507-24 (2005)

Labeikovsky W, Eisenmesser EZ, Bosco D, Kern D “Structure and dynamics of pin1 by NMR” J Mol Biol. 367:1370-81 (2007)

Thai V, Renesto P, Fowler CA, Brown D, Davis T, Gu W, Pollock DD, Kern D, Raoult D, Eisenmesser EZ. “Structural, biochemical, and in vivo studies of the first virally encoded cyclophilin from the Mimivirus” J Mol Biol. 378, 71-86 (2008)

Davis T, Walker J, Ouyang H, Mackenzie F, Newman E, Eisenmesser EZ, Dhe-Paganon S “The Crystal Structure of Human WD40-Repeat Domain Peptidyl-Prolyl Isomerase” FEBS, 275, 2283-95 (2008).

Kovacs JM, Hannan JP, Eisenmesser EZ, Holers VM. ”Mapping of the C3D ligand binding site on complement receptor 2 (CR2/CD21) using nuclear magnetic resonance and chemical shift analysis “ J. Biol Chem. 284, 9513-9520 (2009).

Schlegel J, Armstrong G, Redzic JS, Zhang F, and Eisenmesser EZ. “Characterizing and controlling the inherent dynamics of cyclophilin-A” Protein Science 18, 811-824 (2009).

Schlegel J, Redzic JS, Porter CC, Yurchenko V, Bukrinsky M, Armstrong GS, Zhang F, Isern NG, DeGregori J, Hodges R, Eisenmesser EZ. “Solution characterization of the extracellular region of EMMPRIN/CD147 and its interaction with its enzyme ligand cyclophilin-A”. J Mol Biol., 18, 518-535 (2009).

Clarkson MW, Lei M, Eisenmesser EZ, Labeikovsky W, Redfield A, Kern D “Mesodynamics in the SARS nucleocapsid measured by NMR field cycling” J. Biomol. NMR 45:217-225 (2009).

Gardino AK, Villali J, Kivenson A, Lei M, Liu CF, Steindel P, Eisenmesser EZ, Labeikovsky W, Wolf-Watz M, Clarkson MW, Kern D. “Transient non-native hydrogen bonds promote activation of a signaling protein.” Cell 11:139(6):1049-1051 (2009).

Yurchenko V, Constant S, Eisenmesser EZ, Bukrinsky M. “Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics.” Clin Exp Immunol. 160(3):305-317 (2010).

Kovacs JM, Hannan JP, Eisenmesser EZ, Holers VM. “Biophysical investigations of complement receptor 2-ligand interactions reveal amino acid contacts unique to each receptor-ligand pair. “ J. Biol Chem. 285(35), 27251-8 (2010).

Davis TL, Walker JR, Campagna-Slater V, Finerty PJ, Paramanathan R, Bernstein G, MacKenzie F, Tempel W, Ouyang H, Lee WH, Eisenmesser EZ, Dhe-Paganon S. “Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases.” PLoS Biol. 8(7):e1000439 (2010).

Bosco DA, Eisenmesser EZ, Clarkson MW, Wolf-Watz M, Labeikovsky W, Millet O, Kern D. “Dissecting the microscopic steps of the cyclophilin A enzymatic cycle on the biological substrate HIV capsid by NMR.” J. Mol Biol. PMID:20708627 (2010).