Ion channels are membrane proteins that control the flow of ions such as K+, Na+, Ca2+, and Cl- across the cell membrane. They regulate many biological processes such as the excitation of nerve and muscle cells, the secretion of hormones, and sensory transduction. In humans, ion channels are found in nearly all tissues and perform a wide variety of tasks. Because of their prevalence and importance in the human body, ion channel dysfunction lies at the heart of a wide range of human pathologies.
Two fundamental properties are central to ion channel function: ion selectivity, whereby only the passage of specific ions is allowed through the channel pore; and channel gating, whereby the opening and closing of the channel pore is regulated in response to a specific stimulus. The research in my lab aims to understand the molecular mechanisms of both channel selectivity and gating in tetrameric cation channels, which comprise the single largest family of ion channels. In these channels, four membrane-spanning subunits or domains form a central pore through which specific ions flow across the cell membrane. To study channel gating, my lab focuses on a group of ligand gated K+ channels that are regulated by a conserved ligand binding domain, the RCK domain. The study of cation channel selectivity is focused on voltage-gated Na+ channels and non-selective cation channels. Our research approach will be a combination of membrane protein crystallography, aimed at determining the three dimensional crystal structures of these channels, and channel electrophysiology, aimed at studying their biophysical properties.
1. Ligand Gating in K+ Channels Ligand-gated K+ channels open in response to the binding of specific ligand molecules. Despite the structural diversity required for different ligands, most ligand binding domains in K+ channels are located at the carboxyl-terminus of the pore, close to the end of the pore-lining inner helices. This common position suggests a general mechanism used to convert chemical energy of ligand binding to the mechanical work of opening the channel.
Analysis of K+ channel sequences reveals that the majority of prokaryotic K+ channels contain a conserved C-terminal ligand-binding domain, named the RCK domain for its role in regulating the conductance of K+. Structure based sequence alignment and mutagenesis studies have shown that RCK domains also exist at the intracellular C-terminal side of the eukaryotic high-conductance Ca2+-gated K+ channels (BK or maxiK) as two tandem copies. The wide distribution of RCK domains in K+ channels highlights their importance in regulating the flow of K+ across the cell membrane. In my laboratory, two RCK-regulated K+ channels are being used as model systems for studying ligand gating in K+ channels: a Ca2+-activated K+ channel, MthK, from the archaebacterium Methanobacterium thermoautotrophicum, and a human high conductance Ca2+-gated K+ channel (hSlo1).
2. Ion Selectivity in Tetrameric Cation Channels Most tetrameric cation channels, including the K+, Ca2+, Na+, and cyclic nucleotide-gated (CNG) channels, are thought to share a similar overall architecture in their ion conduction pore. The details governing their ion selectivity properties, however, are different. Over the last five years tremendous progress has been made in understanding K+ channel selectivity, with the structures of several K+ channels having been solved. There is, however, a severe lack of structural information for other cation channels and, as a result, many of their functional properties, most importantly ion selectivity, are not well understood at the molecular level. Among these channels, the Na+ channel and CNG channels stand out for their extreme physiological importance to humans. Detailed structural and functional information about them would undoubtedly lead to breakthrough discoveries not only in the ion channel field, but medical research as a whole. Another major focus of my research group is elucidating the structural basis of ion selectivity and other functional properties of these two groups of ion channels. Two prokaryotic channels will be used as model systems to study their eukaryotic counterparts: the NaK channel (a prokaryotic non-selective cation channel which is homologous to the ion conduction pore of a CNG channel) and a prokaryotic voltage-gated Na+-selective channel.
RESEARCH INTERESTS
Ligand gating of cation channels
ion selectivity of cation channels
Ion channels and membrane transporters
X-ray crystallography, biochemistry of membrane proteins & electrophysiology
RCK domain mediated gating of Ion Channels
RECENT PUBLICATIONS
Alam A, Shi N & Jiang Y, "Structural Insight into Ca2+ Specificity in Tetrameric Cation Channels" PNAS, 104:15334-15339, 2007
Li Y, Berke I, Chen L & Jiang Y, "Gating and Inward Rectifying Properties of the MthK K+ Channel with and without the Gating Ring" J. Gen Physiol., 129:109-120, 2007
Ye S, Li Y, Chen L, Jiang Y, "Crystal structures of a ligand-free MthK gating ring: insights into the ligand gating mechanism of K+ channels." Cell, 126(6):1161-73, September 2006
Shi N, Ye S, Alam A, Chen L, Jiang Y, "Atomic structure of a Na+- and K+-conducting channel." Nature, 440(7083):570-4, March 2006
Dong J, Shi N, Berke I, Chen L, Jiang Y, "Structures of the MthK RCK domain and the effect of Ca2+ on gating ring stability." J Biol Chem, 280(50):41716-24, December 2005
SIGNIFICANT PUBLICATIONS
Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R, "X-ray structure of a voltage-dependent K+ channel." Nature, 423(6935):33-41, May 2003
Jiang Y, Ruta V, Chen J, Lee A, MacKinnon R, "The principle of gating charge movement in a voltage-dependent K+ channel." Nature, 423(6935):42-8, May 2003
Jiang Y, Lee A, Chen J, Cadene M, Chait BT and MacKinnon R, "Crystal structural and mechanism of a calcium-gated potassium channel" Nature, 417:515-22, 2002
Jiang Y, Lee A, Chen J, Cadene M, Chait BT and MacKinnon R, "Open conformation of potassium channel" Nature, 417:523-6, 2002
Youxing Jiang, Alexander Pico, Martine Cadene, Brian T. Chait, and Roderick MacKinnon, "Structure of the RCK domain from the E. coli K+ channel and demonstration of Its Presence in the Human BK Channel" Neuron, 29:593-601, March 2001
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