title: The crystal structure of the platelet activator aggretin reveals a novel (alphabeta)2 dimeric structure.
abstract: 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 A which reveals a unique tetrameric quaternary structure. The two alphabeta heterodimers are arranged through 2-fold rotational symmetry, resulting in 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 alphabeta 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.
authors.affiliation: Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hooley
authors.forename: Evangelos
authors.initials: E
authors.lastname: Papagrigoriou
authors.forename: Alexei
authors.initials: A
authors.lastname: Navdaev
authors.forename: Amit V
authors.initials: AV
authors.lastname: Pandey
authors.forename: Jeannine M
authors.initials: JM
authors.lastname: Clemetson
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Clemetson
authors.forename: Jonas
authors.initials: J
authors.lastname: Emsley
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014757:Viper Venoms / Q000737:chemistry*
chemical_list: C104778:CLEC2B protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D014757:Viper Venoms; C112292:rhodocytin protein, Calloselasma rhodostoma