Molecular anatomy and molecular design of channel proteins

Abstract

A central goal in membrane biology is to understand how channel proteins work in terms of their underlying protein structures. Ionic channels are symmetric (or pseudosymmetric) transmembrane protein assemblies organized around a central aqueous pore. The two key functional elements are the ionic channel, the actual polar pathway that permits the selective passage of 10(8) ions per second across the apolar core of the membrane lipid bilayer, and the sensor, the structure that detects the stimulus and couples it to the opening or closing (gating) of the channel. The current excitement in membrane protein science emerges from structural information that is providing clues about the molecular determinants of function: molecular cloning and sequencing has led to the elucidation of the primary structures of several superfamilies of voltage-gated and ligand-gated channels; channel proteins have been purified and reconstituted in lipid bilayers with full retention of function; the properties of many channel proteins have been characterized at the single-channel level; cDNA or RNA transcripts have been expressed in oocytes as functional proteins; specific peptide sequences predicted by molecular modeling to form the channel lining have been synthesized by solid-phase methods and proved to be channel formers in lipid bilayers. These advances are beginning to delineate general principles about the molecular design of this class of proteins that are essential for cellular excitability and signal transduction.