Journal
STRUCTURE
Volume 25, Issue 8, Pages 1195-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2017.06.001
Keywords
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Funding
- National Research, Development and Innovation Office (NKFIH) [K108437, K119359]
- Hungarian Academy of Sciences
- National Development Agency [KMOP-4.2.1/B-10-2011]
- National Research, Development and Innovation Fund of Hungary [FIEK_16-1-2016-0005]
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Annexin A2 (ANXA2) has a versatile role in membrane-associated functions including membrane aggregation, endo-and exocytosis, and it is regulated by post-translational modifications and protein-protein interactions through the unstructured N-terminal domain (NTD). Our sequence analysis revealed a short motif responsible for clamping the NTD to the C-terminal core domain (CTD). Structural studies indicated that the flexibility of the NTD and CTD are interrelated and oppositely regulated by Tyr24 phosphorylation and Ser26Glu phospho-mimicking mutation. The crystal structure of the ANXA2-S100A4 complex showed that asymmetric binding of S100A4 induces dislocation of the NTD from the CTD and, similar to the Ser26Glu mutation, unmasks the concave side of ANXA2. In contrast, pTyr24 anchors the NTD to the CTD and hampers the membrane-bridging function. This inhibition can be restored by S100A4 and S100A10 binding. Based on our results we provide a structural model for regulation of ANXA2-mediated membrane aggregation by NTD phosphorylation and S100 binding.
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