Theory-Based Investigations of the Potassium -Selective Ion Channel Protein Family

Abstract

119 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2005.Potassium (K+) channels are important in many life-sustaining processes. The prime motivation of my research has been to develop and expand our knowledge and understanding of K+ channels through hypothesis and computational validation. The research was organized under four dominant themes: uncovering of phylogenetic relationships, conceptualization of relationships of structure, elucidation of relationships through function and physiology, and detailing of the influence of co-evolutionary relationships on modularity. Two principal tools were used: one, theory to generate hypotheses consistent with wide-ranging experimental results, accompanied by mathematical validation: two, recruitment of comparative analysis to sort information inherent in evolutionary processes. The principal findings are: (1) the catalytic domain of potassium channels, namely the permeation pathway, has co-evolved with its regulatory domain. This bears the following important implications: (i) the catalytic domain is not functionally modular; (ii) the catalytic domain is subfamily-specific, which promises a revolutionary technique for the function annotation of a protein family based on evolutionary similarity in the structural scaffold of the active site. Also detailed is a method for the characterization of genome-complements of protein families. (2) identification of numerous residue segments which underlie individual conduction events and impart subfamily-specific phenotypes. In particular, we analyzed differences in the structurally important elements in the pore helix and the inner helix of various K+ channel subfamilies, and theorized the importance of each observation with regard to physiology and channel function. (3) analysis of evolutionary relationships has revealed the order of emergence of various classes of subfamilies, explained the origin of the two-pore channels, and raised an interesting research avenue for exploring beta subunits. We also demonstrated the conservation of K+ channels across all life, and a method for visualizing large phylogenies. (4) structural modeling of hERG K+ channels which are the subject of great pharmacological interest. (5) discovery of new intracellular locations, namely the mitochondrion, for a specific isoform of plant sucrose synthases, namely the SH1 isoform. This discovery seems to explain the pattern of their altered localization in anoxic conditions, and suggests an important role for sucrose synthases in plant cell adaptation to oxygen availability.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD