Irina I. Serysheva, Ph.D.
Associate Professor


Description of Research

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.

The ability of cells to maintain low levels of Ca2+ under resting conditions and to create rapid and transient increases in Ca2+ upon stimulation is a fundamental property of cellular Ca2+ signaling mechanism. An increase of cytosolic Ca2+ level in response to diverse stimuli is largely accounted for by the inositol 1,4,5-trisphosphate receptor (IP3R) present in the endoplasmic reticulum membranes of virtually all eukaryotic cells. Extensive information is currently available on the function of IP3Rs and their interaction with modulators. Very little, however, is known about their molecular architecture and therefore most critical issues surrounding gating of IP3R channels are still ambiguous, including the central question of how opening of the IP3R pore is initiated by IP3 and Ca2+. Membrane proteins such as IP3R channels have proven to be exceptionally difficult targets for structural analysis due to their large size, their location in the membrane environment, and their dynamic nature. To date, a 3D structure of complete IP3R channel is determined by single-particle cryo-EM at intermediate resolution, and the best crystal structures of IP3R are limited to a soluble portion of the cytoplasmic region representing ∼15% of the entire channel protein. Together these efforts provide the important structural information for this class of ion channels and serve as the basis for further studies aiming at understanding of the IP3R function.

An increase of cytosolic Ca2+ level in response to diverse stimuli is largely accounted for by the inositol 1,4,5-trisphosphate receptor (IP3R) present in the endoplasmic reticulum membranes of virtually all eukaryotic cells. Extensive information is currently available on the function of IP3Rs and their interaction with modulators. Very little, however, is known about their molecular architecture and therefore most critical issues surrounding gating of IP3R channels are still ambiguous, including the central question of how opening of the IP3R pore is initiated by IP3 and Ca2+. To date, a 3D structure of complete IP3R channel is determined by single-particle cryo-EM at intermediate resolution, and the best crystal structures of IP3R are limited to a soluble portion of the cytoplasmic region representing ∼15% of the entire channel protein. Together these efforts provide the important structural information for this class of ion channels and serve as the basis for further studies aiming at understanding of the IP3R function.

Contact Information

Irina.I.Serysheva@uth.tmc.edu

UTHealth Medical School
Department of Biochemistry and Molecular Biology
6431 Fannin Street, MSB 6.219
Houston, Texas 77030

713-500-5523 Direct  713-500-0652 Fax

Education

Ph.D. - A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia

Postdoctoral Fellow - Moscow State University, Russia

Research Interests

Structure and Function of Calcium Channels

Publications

Toward a high-resolution structure of IP3R channel

Serysheva II. Cell Calcium. 2014 Sep;56(3):125-132. doi: 10.1016/j.ceca.2014.08.002

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Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel.

Serysheva II, Ludtke SJ, Baker ML, Cong Y, Topf M, Eramian D, Sali A, Hamilton SL, Chiu W.

Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9610-5. doi: 10.1073/pnas.0803189105. Epub 2008 Jul 10.

PMID: 18621707

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Flexible architecture of IP3R1 by Cryo-EM.

Ludtke SJ, Tran TP, Ngo QT, Moiseenkova-Bell VY, Chiu W, Serysheva II.

Structure. 2011 Aug 10;19(8):1192-9. doi: 10.1016/j.str.2011.05.003.

PMID: 21827954

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Validation of Cryo-EM Structure of IP3R1 Channel.

Murray SC, Flanagan J, Popova OB, Chiu W, Ludtke SJ, Serysheva II.

Structure. 2013 Jun 4;21(6):900-9. doi: 10.1016/j.str.2013.04.016. Epub 2013 May 23.

PMID: 23707684

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Single-particle Cryo-EM of calcium release channels: structural validation.

Ludtke SJ, Serysheva II.

Curr Opin Struct Biol. 2013 Oct;23(5):755-62. doi: 10.1016/j.sbi.2013.06.003. Epub 2013 Jul 5.

PMID: 23831288

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Single-particle cryo-EM of the ryanodine receptor channel in an aqueous environment

Baker MR, Fan G, Serysheva II. Eur J Transl Myol. 2015;25(1):35-48.

PMID: 438180

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Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia

Jarius S, Scharf M, Begemann N, Stöcker W, Probst C, Serysheva II, Nagel S, Graus F, Psimaras D, Wildemann B and Komorowski L. Journal of Neuroinflammation (2014) 11:206. DOI 10.1186/s12974-014-0206-3.

PMID: 4300617

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