dc.contributor.advisor | Hwang, Tzyh-Chang | eng |
dc.contributor.author | Wang, Xiaohui, 1971- | eng |
dc.date.issued | 2009 | eng |
dc.date.submitted | 2009 Fall | eng |
dc.description | The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. | eng |
dc.description | Title from PDF of title page (University of Missouri--Columbia, viewed on January 25, 2011). | eng |
dc.description | Vita. | eng |
dc.description | Thesis advisor: Tzyh-Chang Hwang. | eng |
dc.description | "Dec 2009" | eng |
dc.description | Ph. D. University of Missouri-Columbia 2009. | eng |
dc.description.abstract | The chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR) has two membrane spanning domains (MSD), forming the channel pore, and two nucleotide binding domains (NBD), controlling the channel gating (opening and closing). The CFTR also has a unique regulatory (R) domain. After the CFTR is phosphorylated at R domain, gating of the phosphorylated CFTR is coupled to ATP binding and hydrolysis at CFTR's two NBDs. However, the role of dimerization in channel gating is unknown. We first investigated whether two ATP binding sites play an equivalent role in the dynamics of NBD dimerization, therefore in gating CFTR channels. By identifying two critical aromatic amino acids that coordinate the adenine ring of the bound ATP, we conclude that opening of the channel is initiated by ATP binding at the NBD2 site, and tighter binding at W401 at the NBD1 site prolongs channel open time. We then studied the role of signature sequence in channel gating. We found that micromolar [Cd2+] can dramatically increase the activity of G551D-CFTR. A specific region of the signature sequence is found to result in positive response to Cd2+. We thus conclude that signature sequence serves as a switch that transmits the signal of Cd2+ binding to the gate opening. The Cd2+ effect is found to work through forming a metal bridge connecting G551D/C to unknown cysteine residue in CFTR. Our data provide the first evidence that R domain is involved in the CFTR channel opening, besides its role in PKA-dependent phosphorylation. | eng |
dc.description.bibref | Includes bibliographical references. | eng |
dc.format.extent | x, 120 pages | eng |
dc.identifier.oclc | 698373044 | eng |
dc.identifier.uri | https://hdl.handle.net/10355/9866 | |
dc.identifier.uri | https://doi.org/10.32469/10355/9866 | eng |
dc.language | English | eng |
dc.publisher | University of Missouri--Columbia | eng |
dc.relation.ispartofcommunity | University of Missouri--Columbia. Graduate School. Theses and Dissertations | eng |
dc.rights | OpenAccess. | eng |
dc.rights.license | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. | |
dc.subject.mesh | Cystic Fibrosis Transmembrane Conductance Regulator -- physiology | eng |
dc.subject.mesh | Ion Channel Gating -- physiology | eng |
dc.subject.mesh | Cystic Fibrosis Transmembrane Conductance Regulator -- genetics | eng |
dc.subject.mesh | Adenosine triphosphate -- metabolism | eng |
dc.subject.mesh | Binding sites | eng |
dc.subject.mesh | Nucleotides -- Metabolism | eng |
dc.subject.mesh | Cadmium -- Metabolism | eng |
dc.title | CFTR gating mechanism : the role of dimerization of nucleotide binding domains | eng |
dc.type | Thesis | eng |
thesis.degree.discipline | Medical Pharmacology and Physiology (MU) | eng |
thesis.degree.grantor | University of Missouri--Columbia | eng |
thesis.degree.level | Doctoral | eng |
thesis.degree.name | Ph. D. | eng |