Transfer of ions across biological membranes is central to physiological processes like nerve excitation, muscle cell contraction, signal transduction and hormone secretion. Ion channels play a vital role by providing a passageway, the ion conduction pore, within membranes to allow specific ions to traverse down their electrochemical gradient. In humans, ion channels are found in nearly all tissues serving a variety of physiologically essential functions. Because of their prevalence and importance in the human body, dysfunction of a channel is often to blame for a wide range of human pathologies. The ability to select for specific ionic species is known as ion selectivity and is a fundamental property defining ion channel function. In tetrameric cation channels, which comprise the single largest family of ion channels including the K+, Ca2+, Na+, and cyclic nucleotide-gated (CNG) channels, selectivity is usually a direct consequence of the unique structural and chemical environment within part of the ion channel pore, the selectivity filter, which is distinct among different channels. Our understanding of the molecular details governing ion selectivity in this group of channels has come a long way with the advancement of genetic, biochemical, and electrophysiological analysis of ion channels and, more recently, the structural characterization of several members beginning with the ground breaking work of the KcsA K+ channel structure and subsequent work on other K+ selective channels. Although these structural studies offer a direct visualization of the selectivity filter of K+ channels, the determinant factors contributingto K+ selectivity are still under heated debate. Moreover, there is little structural information available for other tetrameric cation channels and the molecular basis for their ion selectivity remains unclear. The overall goal of our research is to understand the structural basis of ion selectivity in tetrameric cation channels. Taking advantage of the extremely high resolution crystal structures of several model proteins representing the ion conduction pores of both selective and non-selective channels, we aim to elucidate basic principles of ion selectivity in two groups of physiologically essential cation channels. One is the non-selective, Ca2+ permeable cyclic nucleotide-gated (CNG) channels, using NaK from Bacillus cereus and its CNG- mimicking chimeras as model systems;the other is K+ selective channels, using a K+ selective NaK mutant (NaK2K) and the MthK K+ channel from Methanobacterium thermoautotrophicum as model systems. A combined approach of protein crystallography, electrophysiology and protein chemical synthesis will be employed in the proposed studies
Ion channels control the transfer of ions across cell membranes, a biological process central to nerve excitation, muscle cell contraction, signal transduction, and hormone secretion. Not surprisingly, given their central role in much of our biological functioning, defects in these channels lead to a variety of disabling human disorders. Diseases such as certain forms of seizures, deafness, ataxia, and cardiac arrhythmias, for instance, are directly attributable to ion channel dysfunction.
| She, Ji; Guo, Jiangtao; Chen, Qingfeng et al. (2018) Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel. Nature 556:130-134 |
| Nguyen, Nam X; Armache, Jean-Paul; Lee, Changkeun et al. (2018) Cryo-EM structure of a fungal mitochondrial calcium uniporter. Nature 559:570-574 |
| Guo, Jiangtao; Zeng, Weizhong; Jiang, Youxing (2017) Tuning the ion selectivity of two-pore channels. Proc Natl Acad Sci U S A 114:1009-1014 |
| Guo, Jiangtao; She, Ji; Zeng, Weizhong et al. (2017) Structures of the calcium-activated, non-selective cation channel TRPM4. Nature 552:205-209 |
| Lee, Changkeun; Guo, Jiangtao; Zeng, Weizhong et al. (2017) The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. Nature 547:472-475 |
| Chen, Qingfeng; She, Ji; Zeng, Weizhong et al. (2017) Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature 550:415-418 |
| Guo, Jiangtao; Zeng, Weizhong; Chen, Qingfeng et al. (2016) Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana. Nature 531:196-201 |
| Liao, Jun; Marinelli, Fabrizio; Lee, ChangKeun et al. (2016) Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger. Nat Struct Mol Biol 23:590-599 |
| Lam, Yee Ling; Zeng, Weizhong; Derebe, Mehabaw Getahun et al. (2015) Structural implications of weak Ca2+ block in Drosophila cyclic nucleotide-gated channels. J Gen Physiol 146:255-63 |
| Lam, Yee Ling; Zeng, Weizhong; Sauer, David Bryant et al. (2014) The conserved potassium channel filter can have distinct ion binding profiles: structural analysis of rubidium, cesium, and barium binding in NaK2K. J Gen Physiol 144:181-92 |
Showing the most recent 10 out of 20 publications
