An alternative N-terminal fold of the intestine-specific annexin A13a induces dimerization and regulates membrane-binding.

McCulloch KM, Yamakawa I, Shifrin DA, McConnell RE, Foegeding NJ, Singh PK, Mao S, Tyska MJ, Iverson TM
J Biol Chem. 2019 294 (10): 3454-3463

PMID: 30610115 · PMCID: PMC6416438 · DOI:10.1074/jbc.RA118.004571

Annexin proteins function as Ca-dependent regulators of membrane trafficking and repair that may also modulate membrane curvature. Here, using high-resolution confocal imaging, we report that the intestine-specific annexin A13 (ANX A13) localizes to the tips of intestinal microvilli and determined the crystal structure of the ANX A13a isoform to 2.6 Å resolution. The structure revealed that the N terminus exhibits an alternative fold that converts the first two helices and the associated helix-loop-helix motif into a continuous α-helix, as stabilized by a domain-swapped dimer. We also found that the dimer is present in solution and partially occludes the membrane-binding surfaces of annexin, suggesting that dimerization may function as a means for regulating membrane binding. Accordingly, as revealed by binding and cellular localization assays, ANX A13a variants that favor a monomeric state exhibited increased membrane association relative to variants that favor the dimeric form. Together, our findings support a mechanism for how the association of the ANX A13a isoform with the membrane is regulated.

© 2019 McCulloch et al.

MeSH Terms (17)

Animals Annexins Cell Membrane Epithelial Cells Humans Hydrogen-Ion Concentration Intestinal Mucosa Intestines Liposomes Mice Models, Molecular Organ Specificity Protein Binding Protein Conformation, alpha-Helical Protein Multimerization Protein Structure, Quaternary Protein Transport

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