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Crystal structure of the S100A4-nonmuscle myosin IIA tail fragment complex reveals an asymmetric target binding mechanism.

Artikel i vetenskaplig tidskrift
Författare Bence Kiss
Annette Duelli
László Radnai
Katalin A Kékesi
Gergely Katona
László Nyitray
Publicerad i Proceedings of the National Academy of Sciences of the United States of America
Volym 109
Nummer/häfte 16
Sidor 6048-53
ISSN 1091-6490
Publiceringsår 2012
Publicerad vid Institutionen för kemi och molekylärbiologi
Sidor 6048-53
Språk en
Länkar dx.doi.org/10.1073/pnas.1114732109
Ämnesord cancer, metastasis, calcium, motor protein, protein binding
Ämneskategorier Strukturbiologi, Molekylärbiologi, Tumörbiologi

Sammanfattning

S100A4 is a member of the S100 family of calcium-binding proteins that is directly involved in tumor metastasis. It binds to the nonmuscle myosin IIA (NMIIA) tail near the assembly competence domain (ACD) promoting filament disassembly, which could be associated with increasing metastatic potential of tumor cells. Here, we investigate the mechanism of S100A4-NMIIA interaction based on binding studies and the crystal structure of S100A4 in complex with a 45-residue-long myosin heavy chain fragment. Interestingly, we also find that S100A4 binds as strongly to a homologous heavy chain fragment of nonmuscle myosin IIC as to NMIIA. The structure of the S100A4-NMIIA complex reveals a unique mode of interaction in the S100 family: A single, predominantly α-helical myosin chain is wrapped around the Ca(2+)-bound S100A4 dimer occupying both hydrophobic binding pockets. Thermal denaturation experiments of coiled-coil forming NMIIA fragments indicate that the coiled-coil partially unwinds upon S100A4 binding. Based on these results, we propose a model for NMIIA filament disassembly: Part of the random coil tailpiece and the C-terminal residues of the coiled-coil are wrapped around an S100A4 dimer disrupting the ACD and resulting in filament dissociation. The description of the complex will facilitate the design of specific drugs that interfere with the S100A4-NMIIA interaction.

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