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


McCulloch KMKathryn M , Yamakawa IIzumi , Shifrin DADavid A , McConnell RERussell E , Foegeding NJNora J , Singh PKPrashant K , Mao SSuli , Tyska MJMatthew J , Iverson TMT M . The Journal of biological chemistry. 2019 1 4; ().


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 (ANXA13) localizes to the tips of intestinal microvilli and determined the crystal structure of the ANXA13a isoform to 2.6 Å resolution. The structure revealed that the N terminus exhibits an alternative fold that converts the first two helices and 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, ANXA13a 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 ANXA13a isoform with the membrane is regulated.