Vann Bennett, M.D., Ph.D.
(Johns Hopkins School of Medicine)

James B. Duke Professor, Departments of Cell Biology, Biochemistry, and Neurobiology

Investigator, Howard Hughes Medical Institute

Programs: CMB, Molecular Cancer Biology

A major goal of this laboratory is to understand how vertebrate cells organize their plasma membranes into functional domains. Our research began with discovery of the ankyrin family of membrane-adapters. Ankyrins couple a variety of ion transporters and cell adhesion molecules to spectrin, and organize these proteins into specialized membrane domains. Ankyrin-dependent membrane domains include excitable membranes in neurons and heart, lateral membranes of epithelia and early embryos, sensory cilia of photoreceptors, costameres of skeletal and heart muscle and the neuromuscular junction. Ankyrins interact with cytoplasmic domains of their membrane-partners through ANK repeats, which are folded as a solenoid and contain a groove along their surface. Ankyrin-binding activity has developed independently at least 10 times in metazoan evolution. Binding depends on a simple code: 10-20 amino acids with an unstructured conformation but otherwise no other obvious consensus.

We have made several discoveries establishing a conserved physiological function of ankyrins and their clinical significance in brain and heart. We have identified a cardiac arrhythmia syndrome associated with sudden cardiac death that is caused by loss-of function mutations in ankyrin-B, and have a mouse model for this syndrome. We also have discovered that ankyrin-G is the central organizer of axon initial segments, which are sites where action potentials are generated in the nervous system. Ankyrin-G coordinates voltage-gated Na channels, responsible for initiating axon potentials, KCNQ2/3 channels that modulate voltage-gated Na channel activity, neurofascin, which forms interneuron synapses, and beta-4 spectrin, which couples membrane proteins to the cytoskeleton. We have discovered that a mutation in the ankyrin-binding site of the cardiac voltage-gated sodium channel (Nav1.5) causes Brugada syndrome (a form of cardiac arrhythmia) and loss of targeting of Nav1.5 to the cell surface of cardiomyocytes. These studies demonstrate a requirement for ankyrins in localization of a variety of ion channels in excitable membranes in the heart and nervous system, and suggest a new class of functional channelopathies due to abnormal cellular localization.

We have discovered essential roles of the ankyrin pathway in specialized membrane domains of epithelial cells, skeletal muscle, and rod photoreceptors. Ankyrin-G is a molecular partner for the cell adhesion molecule E-cadherin at sites of cell-cell contact in early embryos and epithelial cells. Moreover, ankyrin-G and beta-2 spectrin are key elements of a mechanism responsible for biogenesis and maintenance of the lateral membrane of cultured epithelial cells. Ankyrin-B and ankyrin-G collaborate with microtubules in organization of dystroglycan, an essential cell adhesion molecule, and its associated proteins including dystrophin at costameres and neuromuscular junctions in skeletal muscle. We have also found that ankyrin-B coordinates the Na/K ATPase and Na/Ca exchanger in photoreceptor inner segments while ankyrin-G is required for transport of cyclic nucleotide-gated channels to photoreceptor outer segments. These findings together with work in heart and brain indicate that ankyrin-based domains play major roles in vertebrate physiology.

E-mail
benne012@mc.duke.edu

361 CARL Building
Box 3892 Duke University Medical Center
Durham, NC 27710

Telephone
919-684-3538, 919-684-3105
Fax
919-684-3590

Selected Publications
Sobotzik JM, Sie JM, Politi C, Del Turco D, Bennett V, Deller T, Schultz C (2009) Ankyrin-G is required to maintain axo-dendritic polarity in vivo. Proc Natl Acad Sci U S A. 106:17564-9. -PDF-

Kizhatil K, Baker SA, Arshavsky VY, Bennett V (2009) Ankyrin-G promotes cyclic nucleotide-gated channel transport to rod photoreceptor sensory cilia. Science. 323:1614-7. -PDF-

Kizhatil K, Sandhu NK, Peachey NS, Bennett V (2009) Ankyrin-B is required for coordinated expression of beta-2-spectrin, the Na/K-ATPase and the Na/Ca exchanger in the inner segment of rod photoreceptors. Exp Eye Res. 88:57-64. -PDF-

Davis L, Abdi K, Machius M, Brautigam C, Tomchick DR, Bennett V, Michaely P (2009) Localization and structure of the ankyrin-binding site on beta2-spectrin. J Biol Chem. 284:6982-7. -PDF-

Ayalon, G, Davis, JQ, Scotland, P, Bennett V (2008) An ankyrin-based mechanism for functional organization of dystrophin and dystroglycan. Cell. 135:1189-2000. -PDF-

Bennett V, Healy J. (2008) Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol Med. 14(1):28-36. -PDF-

Abdi KM, Bennett V. (2008) Adducin Promotes Micrometer-Scale Organization of {beta}2-Spectrin in Lateral Membranes of Bronchial Epithelial Cells. Mol Biol Cell. 19(2):536-45. -PDF-

Mohler PJ, Healy JA, Xue H, Puca AA, Kline CF, Allingham RR, Kranias EG, Rockman HA, Bennett V. Ankyrin-B syndrome: enhanced cardiac function balanced by risk of cardiac death and premature senescence. (2007) PLoS ONE. 2(10):e1051. -PDF-

Kizhatil K, Davis JQ, Davis L, Hoffman J, Hogan BL, Bennett V. (2007) Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. J Biol Chem. 282(36):26552-61. -PDF-

Kizhatil K, Yoon W, Mohler PJ, Davis LH, Hoffman JA, Bennett V. (2007) Ankyrin-G and beta2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells. J Biol Chem. 282(3):2029-37. -PDF-

Lee G, Abdi K, Jiang Y, Michaely P, Bennett V, Marszalek PE. (2006) Nanospring behaviour of ankyrin repeats. Nature. 440:246-9. -PDF-

Mohler, PJ, Davis, JQ, Bennett, V. (2005) Ankyrin-B coordinates the Na/K ATPase, Na/Ca exchanger, and InsP3 receptor in a specialized microdomain of cardiac T-tubules. Plos Biology. 3:e423. -PDF-

Mohler, P.J., Splawski, I., Napolitano, C., Botteli, G., Sharpe, L., Timothy, K., Priori, S.G., Keatiing, M.T., and Bennett, V. (2004) A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Nat Acad Sci. USA. 101:9137-42. -PDF-

Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, Bennett V. (2004) Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci USA. 101:17533-8. -PDF-

Mohler, P. J et al. (2003) Ankyrin-B mutation causes type 4 long QT cardiac arrhythmia and sudden cardiac death. Nature. 421:634-639. -PDF-