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Structure. 2017 Aug 1;25(8):1195-1207.e5. doi: 10.1016/j.str.2017.06.001. Epub 2017 Jun 29.

Regulation of the Equilibrium between Closed and Open Conformations of Annexin A2 by N-Terminal Phosphorylation and S100A4-Binding.

Author information

1
Department of Biochemistry, ELTE Eötvös Loránd University, 1117 Budapest, Hungary.
2
Institute of Enzymology, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
3
Institute of Enzymology, Hungarian Academy of Sciences, 1117 Budapest, Hungary; Department of Applied Biotechnology, Budapest University of Technology and Economics, 1117 Budapest, Hungary.
4
Department of Genetics, ELTE Eötvös Loránd University, 1117 Budapest, Hungary; Institute of Physiology, University of Pécs, 7625 Pécs, Hungary.
5
Department of Pharmacology and Pharmacotherapy, University of Pécs, 7624 Pécs, Hungary.
6
MTA-ELTE Research Group of Peptide Chemistry, ELTE Eötvös Loránd University, 1117 Budapest, Hungary.
7
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg 40530, Sweden.
8
Department of Biochemistry, ELTE Eötvös Loránd University, 1117 Budapest, Hungary. Electronic address: nyitray@elte.hu.

Abstract

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 phosphomimicking 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.

KEYWORDS:

Ca(2+) binding; X-ray crystallography; asymmetric interaction; conformational fluctuation; molecular dynamics simulation; protein phosphorylation

PMID:
28669632
DOI:
10.1016/j.str.2017.06.001
[Indexed for MEDLINE]
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