Overview

Functional organization of vertebrate plasma membranes:  Molecules to Physiology

Our laboratory discovered ankyrins and their function in coordinating functionally related membrane-spanning proteins within micron-scale compartments in vertebrate plasma membranes. Ankyrin-dependent compartments include excitable membranes responsible for initiation and propagation of action potentials in the nervous system, and for rhythmic beating of the heart. Cytoplasmic domains of membrane transporters and cell adhesion proteins (15 protein families identified so far) associate on the inner surface of the plasma membrane with members of the ankyrin family.  Ankyrins recognize intrinsically disordered regions within these cytoplasmic domains through independently evolved interactions with a highly conserved extended peptide-binding groove formed by the ANK repeat solenoid.  The ANK repeat solenoid accommodates multiple membrane-spanning partners and can cluster these proteins within nanodomains.  Ankyrins and their partners are in turn 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. Giant ankyrin-G co-evolved with the axon initial segment and myelination, and functions as a master organizer of this domain through recruitment of voltage-gated sodium channels, KCNQ2/3 channels, L1Cam family cell adhesion molecules, beta-4 spectrin, and microtubules. Mutations of ankyrins and spectrins result in human disease including hereditary anemia, cardiac arrhythmia, autism and neurodevelopmental disorders.

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