4.4 Article

The crystal structure of the platelet activator aggretin reveals a novel (αβ)2 dimeric structure

Journal

BIOCHEMISTRY
Volume 47, Issue 30, Pages 7831-7837

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/bi800528t

Keywords

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Funding

  1. British Heart Foundation [RG/07/002/23132] Funding Source: Medline
  2. British Heart Foundation [RG/07/002/23132] Funding Source: researchfish

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Aggretin is a-C-type lectin purified from Calloselasma rhodostoma snake venom. It is a potent activator of platelets, resulting in a collagen-like response by binding and clustering platelet receptor CLEC-2. We present here the crystal structure of aggretin at 1.7 angstrom which reveals a unique tetrameric quaternary structure. The two alpha beta heterodimers are arranged through 2-fold rotational symmetry, resulting in I an antiparallel side-by-side arrangement. Aggretin thus presents two ligand binding sites on one surface and can therefore cluster ligands in a manner reminiscent of convulxin and flavocetin. To examine the molecular basis of the interaction with CLEC-2, we used a molecular modeling approach of docking the aggretin alpha beta structure with the CLEC-2 N-terminal domain (CLEC-2N). This model positions the CLEC-2N structure face down in the saddle-shaped binding site which lies between the aggretin alpha and beta lectin-like domains. A 2-fold rotation of this complex to generate the aggretin tetramer reveals dimer contacts for CLEC-2N which bring the N- and C-termini into the proximity of each other, and a series of contacts involving two interlocking beta-strands close to the N-terminus are described. A comparison with homologous lectin-like domains from the immunoreceptor family reveals a similar but not identical dimerization mode, suggesting this structure may represent the clustered form of CLEC-2 capable of signaling across the platelet membrane.

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