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.
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
Ph.D. - A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia
Postdoctoral Fellow - Moscow State University, Russia
Structure and Function of Calcium Channels
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.
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.
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.