The Faculty

Focus

Ion channels, membrane transport, membrane protein dynamics, energy transduction mechanisms, voltage dependent processes. Over-expression of membrane proteins

Education

Universidad Central de Venezuela, Caracas, Facultad de Ciencias, Licenciado , 1980‑1985, Biology

University of California, Los Angeles, Ph.D., 1987-1990, Physiology

University of California, Los Angeles, Post Doc, 1991-1993, Membrane Biophysics

Biography

May‑Aug 1986 Grass Fellow. Grass Foundation, Marine Biological Laboratory. Woods Hole, Massachusetts.      

1987     Chancellor's Fellow. University of California, Los Angeles

1989     Kugel Foundation Fellow, Department of Physiology, University of California, Los Angeles

1990     John Field Award, Department of Physiology, University of California, Los Angeles, CA.

1991- 1993        PEW Charitable Trust Latin American Fellowship, University of California, Los Angeles, CA.

1994     PPI Program Fellow, Level II. Consejo Nacional de Investigaciones Cientificas y Tecnologicas  (CONICIT) Caracas, Venezuela.

1998-2000         McKnight Fellow, University of Virginia.

2000     SOBLA Prize, Latin-American Society of Biophysicists. Alicante, Spain.

2004     Kuffler/MBL Fellowships. Marine Biological Laboratory, Woods Hole, MA.

2006-present     Pritzker Fellow, The University of Chicago

Research Summary

Most membrane proteins have moving parts that help execute their specific function, often in response to an external stimulus. Our research aims to understand the molecular mechanisms underlying the transduction of different forms of energy into protein motion; in particular the different molecular mechanisms of ion channel gating. We are equally interested in protein structure as in protein dynamics, for it is the dynamic behavior of a molecule what links structure to function.

Therefore, we rely on spectroscopic methods, and in particular reporter group techniques (EPR, Fluorescence), to study channels and other membrane proteins embedded in a fluid lipid bilayer. Static structural analyses are pursued by X-ray crystallography. These structural techniques are all interpreted in the context of high-resolution functional methods (single channel, macroscopic and gating current electro-physiological measurements). Using these strategies, we aim to answer the following long-term questions:

1- What is the structural pathway followed in the transition from the closed to the open conformation in K+ channels, and what is the nature of this conformational wave?

2- What is the influence of the selectivity filter on channel gating?

3- What is the native structure of voltage-dependent channels and how is transmembrane voltage sensed?

4- How do voltage sensor and gate couple to open the channel?

5- What is the molecular basis of mechanosensitivity in prokaryotic channels? How do membrane bilayer deformations are transduced into large protein rearrangements leading to channel opening?

Selected Papers

  1. Cordero-Morales, JF., Jogini, V., Lewis, A., Vásquez, V., Cortes, D.M., Roux, B., and Perozo, E. (2007) Molecular Driving Forces Determining Potassium Channel Slow Inactivation. Nature Structural & Molecular Biology, 14:1062-1069 No PCMID
  2. Cuello, LG, Jogini, V., Cortes, DM, Perozo, E. (2010) Structural mechanism of C-type inactivation in K(+) channels.. Nature 466:203-208 PMCID: PMC3033749
  3. Cuello, LG, Cordero-Morales, J., Jogini, V., Perozo, E. (2010) Structural basis for the coupling between activation and inactivation gates in K(+) channels.. Nature 466:272-275  PMCID: PMC3033755
  4. Cuello LG, Cortes DM, Perozo E. (2004). Molecular architecture of the KvAP voltage-dependent K+ channel in a lipid bilayer. Science. 306(5695):491-5.  No pcmid
  5. Chakrapani, S., Cuello, LG., Perozo, E. (2008) Structural Dynamics of the Isolated-Voltage Sensor Domain of KvAP in Lipid Bilayer. Structure 16(3):398-409 PMCID: PMC2703488
  6. Vásquez, V., Sotomayor, M., Cordero-Morales, J., Schulten, K., and Perozo E. (2008) A Structural Mechanism for MscS Gating in Lipid Bilayers. Science, 321:1210-4. PMCID: PMC2897165
  7. Uysal, S., Vásquez, V., Terechko, V., Esaki, K., Koide, S., Fellouse, FA, Sidhu, SS, Perozo, E. and Kossiakoff, A. (2009) The Crystal Structure of Full-Length KcsA in its Closed Conformation. PNAS 106:6644-9 PMCID: PMC2672561
  8. Dalmas, O., Cuello, LG, Jogini, V., Cortes, DM., Roux, B., Perozo E., (2010) Structural Dynamics of the Magnesium-bound Conformation of CorA in a lipid bilayer. Structure 18: 868-878 PMCID: PMC2935691
  9. Chakrapani, S., Cordero-Morales, JF., Jogini, V., Pan, AC, Cortes, DM, Roux, B., Perozo, E. (2011) On the structural basis of modal gating behavior in K+ channels. Nature Structural & Molecular Biology  18:67-74 PMCID: PMC3059741
  10. Cordero-Morales, JF., Jogini, V., Chakrapani, S., Perozo, E. (2011) A Multipoint Hydrogen Bond Network Underlying KcsA C-type Inactivation. Biophysical Journal, 100(10):2387-2393.  PMCID: PMC3093550
  11. Uysal, S., Cuello, LG., Cortes, DM., Koide, S., Kossiakoff, A., and Perozo, E. (2011) Mechanism of Activation Gating in the Full-Length KcsA K+ Channel. Proc. Natl. Acad. Sci. USA, 108(29):11896-11899. PMCID: PMC3141920
  12. Ferrer-Villada T, Cordero-Morales JF, Arias M, Ficker E, Medovoy D, Perozo E, Tristani-Firouzi M (2011) Molecular coupling in the human ether-a-go-go-related (hERG) K+ channel inactivation pathway. J Biol Chem 286(45):39091-9 PMCID: PMC3234734
  13. Pan AC, Cuello LG, Perozo E, Roux B. (2011) Thermodynamic coupling between activation and inactivation gating in potassium channels revealed by free energy molecular dynamics simulations. J Gen Physiol.138(6):571-80. PMCID: PMC3226968
  14. L. G. Cuello, V. Jogini, D. M. Cortes, A. C. Pan, D. G. Gagnon, O. Dalmas, J. F. Cordero-Morales, S. Chakrapani, B. Roux & E. Perozo. Structural basis for the coupling between activation and inactivation gates in K(+) channels. Nature 466, 272-275, (2010)  PMCID: PMC3033755.
  15. E. Vargas, V. Yarov-Yarovoy, F. Khalili-Araghi, W.A. Catterall, M.L. Klein, M.E, Tarek, K. Lindahl, K. Schulten, E. Perozo, F. Bezanilla, B. Roux. An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. J Gen Physiol. 140(6):587-94. (2012) PMCID: PMC3514734.
  16. Torbeev VY, Raghuraman H, Hamelberg D, Tonelli M, Westler WM, Perozo E, Kent SB. Protein conformational dynamics in the mechanism of HIV-1 protease catalysis..Proc Natl Acad Sci U S A. 108(52):20982-7. PMCID: PMC3248522