Research Interests
Functional organization of vertebrate plasma membranes: Molecules to Physiology
Plasma membrane proteins such as ion transporters, cell adhesion molecules, and signaling receptors all must segregate to specific cell surface compartments to perform their physiological roles. Our laboratory has discovered ankyrin and adducin and their roles together with their partner spectrin in a mechanism that is responsible for coordinating functionally related membrane-spanning proteins within micron-scale domains in diverse vertebrate plasma membranes. These membrane domains include excitable membranes in the brain and heart, lateral membranes of epithelial cells, and costameres in striated muscle. Ankyrins recognize intrinsically disordered regions in cytoplasmic domains of membrane transporters and cell adhesion proteins (15 protein families identified so far) through independently evolved interactions with a highly conserved peptide-binding groove formed by the ANK repeat solenoid. Ankyrins are coupled to spectrins, which are elongated organelle-sized proteins that form mechanically resilient networks on the cytoplasmic surfaces of plasma membrane domains. Spectins are cross-linked by actin protofilaments capped on their fast-growing ends by adducin. In addition, giant vertebrate ankyrins with specialized roles in neurons acquired new coding sequences by exon shuffling early in vertebrate evolution. Mutations of ankyrins and spectrins result in human disease including hereditary anemia, cardiac arrhythmia, autism and neurodevelopmental disorders