Irina I. Serysheva, PhD

Areas of Interest

Research Interests

Structure-Function of Ion Channels

Cellular Ca²⁺ Signaling

Membrane Transport

Electron Cryo-microscopy

Image Processing and 3D Reconstruction

Structure Determination of Macromolecular Complexes

Structural Proteomics

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 cryo-EM structure determination pipeline that allows for solving atomic resolution structures of biological assemblies in different functional states.

Selected Publications

Fan G, Baker ML, Wang Z, Baker MR,Sinyagovskiy PA, Chiu W, Ludtke SJ, Serysheva II. 2015. Gating machinery of InsP3R channels revealed by electron cryomicroscopy. Nature. 52:336-441.29.

Fan G, Baker MR, Wang Z, Seryshev AB, Ludtke SJ, Baker ML, Serysheva II. 2018. Cryo-EM Reveals Ligand Induced Allostery Underlying InsP3R Channel Gating. Cell Research. 28: 1158-1170.31.

Baker MR, Fan G., Seryshev AB, Agosto MA., Baker ML, Serysheva II. 2021. Cryo-EM structure of type 1 IP3R channel in a lipid bilayer. Communications Biology. 4:625.

Arige V, Terry LE, Wagner LE, Malik S, Baker MR, Fan G., Joseph SK, Serysheva II, Yule DI. 2022. Functional determination of calcium-binding sites required for the activation of inositol 1,4,5-trisphosphate receptors. PNAS USA. 119(39).