Dr. Irina Serysheva, Associate Professor

Dr. Serysheva

Department of Biochemistry and Molecular Biology

University of Texas-Houston Medical School
P.O. Box 20708 - Houston, Texas 77225
Office:(713) 500-5523
FAX: (713) 500-6297
email: Irina.I.Serysheva@uth.tmc.edu

Ph.D., A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia
B.S., M.S., Moscow State University, Moscow, Russia

STRUCTURE AND FUNCTION OF INTEGRAL MEMBRANE PROTEINS

Our research aims to understand molecular mechanisms underlying transport of molecules into and out of the cell across the surface membrane, or between different intracellular compartments through structure-functional studies of integral membrane proteins known as ion channels, and the macromolecular complexes they form. Ion channels regulate many diverse biological functions that include muscle contraction, hormone secretion, gene transcription, metabolic regulation, neurotransmitter release, fertilization and apoptosis. The knowledge about the three dimensional (3D) architecture of ion channels is required to understand molecular basis of ion channel gating (opening/closing process), and how this process is controlled by a wide variety of endogenous molecules and pharmacological modifies. To answer these questions we use a combination of electron microscopy and computer reconstruction techniques in conjunction with biochemical, electrophysiological and molecular biological approaches. Our structure research efforts include: 1) purification of ion channels from natural sources or from high-level expression systems; 2) electron cryomicroscopy (cryo-EM) of the purified channel assemblies; 3) computer image processing and 3D reconstruction; 4) structure analysis and annotation using combination of visualization and computational tools; 5) prediction of functional roles of the identified structural domains via bioinformatics.

Recent focus has been on structural analysis of Ca²⁺ channels that mediate ligand-gated release of Ca²⁺ from intracellular stores: the ryanodine-sensitive Ca²⁺ release channel (RyR), the primary Ca²⁺ release channel in muscle cells, and the inositol 1,4,5-trisphosphate-sensitive Ca²⁺ release channel (IP₃R), localized in the endoplasmic reticulum. Both channels are large tetrameric protein complexes with a molecular mass of ~2.3 MDa for RyRs and 1.2 MDa for IP₃Rs. Defects in these channel proteins cause abnormal regulation of cell Ca²⁺ level underlying numerous human diseases: Malignant Hyperthermia, Central Core disease, cardiac hypertrophy, heart failure, hereditary ataxias, Huntington’s disease, Alzheimer’s disease, osteoporosis, atherosclerosis and some migraines.

RyR1 figure

The 9.6 Å-resolution structure of the RyR1Ca²⁺ release channel in its closed conformation was resolved by using electron cryomicroscopy and computer reconstruction techniques. Two opposing RyR1 subunits from the channel tetramer are shown in a side view. 41 -helices are annotated as cylinders colored according to their locations in the map. 7 -sheets are shown as orange surfaces (Serysheva et al., PNAS 2008).

Selected References

Hamilton SL, Serysheva I.I. (2009) Ryanodine receptor structure: progress and challenges. J Biol Chem. 284:4047-4051.

Serysheva, I. I., Ludtke, S. J., Baker, M. L., Y. Cong, Y., Topf, M., Eramian, D., Sali, A., S. L. Hamilton, S. L. and Chiu, W. (2008). Subnanometer-esolutuion electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel. PNAS USA 105, 9610-9615.

Moiseenkova-Bell, V.Y., Stanciu, L. A., Serysheva, I. I., Tober, B. and Wensel, T. G. (2008). Structure of TRPV1 channel revealed by electron cryomicroscopy. PNAS USA 105, 7451-7455.

Serysheva, I. I., Chiu, W. and Ludtke, S. J. (2007) Single Particle Electron Cryomicroscopy of the Ion Channels in the Excitation-Contraction Coupling Junction, in “Cellular Electron Microscopy, ed. J. Richard McIntosh, (Series “Methods in Cell Biology”), Elsevier Academic Press, 407-435.

Ludtke, S. J., Serysheva, I. I., Hamilton, S. L. and Chiu, W. (2005) The Pore Structure of the closed RyR1 Channel. Structure 13, 1203 -1211.

Serysheva, I. I., Hamilton, S. L., Chiu, W. and Ludtke, L. J. (2005) Structure Ca²⁺ Release Channel at 14-Å Resolution. J. Mol. Biol. 345, 427-431.

Serysheva, I. I. (2004) Structural Insights into Excitation-Contraction Coupling by Electron Cryomicroscopy. Biochem. 69, 1226-1232.

Serysheva, I. I., D. J. Bare, S. L. J. Ludtke, C. A. Kettlun, W. Chiu & G. L. Mignery (2003) Structure of the Type 1 Inositol 1,4,5-trisphosphate Receptor Revealed by Electron Cryomicroscopy. J. Biol. Chem. 278, 21319-21322.

Baker M. L., Serysheva, I. I., Sencer, S., Wu, Y., Ludtke, S. J., Jiang, W., Hamilton, S. L. and Chiu, W. (2002) The skeletal muscle Ca²⁺ release channel has an oxidoreductase-like domain. PNAS 99,12155 -12160.

Serysheva, I. I., Ludtke, S. L., Baker, M. R., Chiu, W. and Hamilton, S. L. (2002) Structure of the voltage-gated L-type Ca²⁺ channel by electron cryo-microscopy. PNAS 99, 10370-10375.

Serysheva, I. I., Schatz, van Heel, M., Chiu, W. and Hamilton, S. L. (1999) Structure of the Skeletal Muscle Calcium Release Channel Activated with Ca²⁺ and AMP-PCP. Biophys. J. 77, 1936-1944.

Orlova, E.V., I. I. Serysheva, I. I., van Heel, M., Hamilton, S. L. and Chiu, W. (1996) Two structural configurations of the skeletal muscle calcium release channel. Nature Struct. Biol. 3, 547-552.

Serysheva I. I., Orlova, E. V., Chiu, W., Sherman, M. B., Hamilton, S. L. and van Heel, M. (1995) Electron cryomicroscopy and angular reconstitution used to visualize the skeletal muscle calcium release channel. Nature Struct. Biol. 2,18-24.

Search PubMed for a complete list of Dr. Serysheva's publications.

About BMB

Meet the BMB Faculty Members

Dr. Irina Serysheva, Associate Professor

STRUCTURE AND FUNCTION OF INTEGRAL MEMBRANE PROTEINS