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J Biol Chem. 2019 Mar 8;294(10):3454-3463. doi: 10.1074/jbc.RA118.004571. Epub 2019 Jan 4.

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

Author information

1
From the Departments of Pharmacology.
2
Cell and Developmental Biology, and.
3
From the Departments of Pharmacology, tina.iverson@vanderbilt.edu.
4
Biochemistry.
5
the Center for Structural Biology, and.
6
the Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232.

Abstract

Annexin proteins function as Ca2+-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 in vitro 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.

KEYWORDS:

annexin; calcium regulation; intestinal microvilli; membrane curvature; membrane fusion; oligomerization; protein folding; protein structure; structure-function

PMID:
30610115
DOI:
10.1074/jbc.RA118.004571

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