title: A single divergent exon inhibits ankyrin-B association with the plasma membrane.
abstract: Vertebrate ankyrin-B and ankyrin-G exhibit divergent subcellular localization and function despite their high sequence and structural similarity and common origin from a single ancestral gene at the onset of chordate evolution. Previous studies of ankyrin family diversity have focused on the C-terminal regulatory domain. Here, we identify an ankyrin-B-specific linker peptide connecting the ankyrin repeat domain to the ZU52-UPA module that inhibits binding of ankyrin-B to membrane protein partners E-cadherin and neurofascin 186 and prevents association of ankyrin-B with epithelial lateral membranes as well as neuronal plasma membranes. The residues of the ankyrin-B linker required for autoinhibition are encoded by a small exon that is highly divergent between ankyrin family members but conserved in the ankyrin-B lineage. We show that the ankyrin-B linker suppresses activity of the ANK repeat domain through an intramolecular interaction, likely with a groove on the surface of the ANK repeat solenoid, thereby regulating the affinities between ankyrin-B and its binding partners. These results provide a simple evolutionary explanation for how ankyrin-B and ankyrin-G have acquired striking differences in their plasma membrane association while maintaining overall high levels of sequence similarity.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: He
authors.forename: Wei-Chou
authors.initials: WC
authors.lastname: Tseng
authors.forename: Vann
authors.initials: V
authors.lastname: Bennett
mesh_terms: D000818:Animals; D017089:Ankyrin Repeat; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D005091:Exons / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology
chemical_list: C498994:ANK2 protein, human; C490613:ANK3 protein, human; D017487:Ankyrins; D015820:Cadherins; D015815:Cell Adhesion Molecules; C054305:NFASC protein, human; D009414:Nerve Growth Factors
keywords: Ankyrin Diversity; Autoinhibition; Epithelial Cell; Evolution; Intramolecular Interaction; Neurons; Plasma Membrane; Transfection