| Structural highlights
Function
[AGGB_CALRH] Elicits platelet aggregation by the binding to the C-type lectin domain family 1 member B (CLEC1B/CLEC2). Binding leads to tyrosine phosphorylation in the cytoplasmic tail of CLEC1B, which promotes the binding of spleen tyrosine kinase (Syk), subsequent activation of PLCgamma2, and platelet activation and aggregation. Binding to GPIbalpha (GP1BA) and alpha2/beta-1 (ITGA2/ITGB1) may also induce aggregation, but this is controversial.[1] [2] [3] [4] [5] [6] [7] [8]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
The crystal structure of the platelet activator aggretin reveals a novel (alphabeta)2 dimeric structure.,Hooley E, Papagrigoriou E, Navdaev A, Pandey AV, Clemetson JM, Clemetson KJ, Emsley J Biochemistry. 2008 Jul 29;47(30):7831-7. Epub 2008 Jul 3. PMID:18597489[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Navdaev A, Clemetson JM, Polgar J, Kehrel BE, Glauner M, Magnenat E, Wells TN, Clemetson KJ. Aggretin, a heterodimeric C-type lectin from Calloselasma rhodostoma (Malayan pit viper), stimulates platelets by binding to alpha2beta1 integrin and glycoprotein Ib, activating Syk and phospholipase Cgamma 2, but does not involve the glycoprotein VI/Fc receptor gamma chain collagen receptor. J Biol Chem. 2001 Jun 15;276(24):20882-9. Epub 2001 Apr 3. PMID:11287424 doi:http://dx.doi.org/10.1074/jbc.M101585200
- ↑ Shin Y, Morita T. Rhodocytin, a functional novel platelet agonist belonging to the heterodimeric C-type lectin family, induces platelet aggregation independently of glycoprotein Ib. Biochem Biophys Res Commun. 1998 Apr 28;245(3):741-5. PMID:9588185 doi:http://dx.doi.org/10.1006/bbrc.1998.8516
- ↑ Wang R, Kong C, Kolatkar P, Chung MC. A novel dimer of a C-type lectin-like heterodimer from the venom of Calloselasma rhodostoma (Malayan pit viper). FEBS Lett. 2001 Nov 23;508(3):447-53. PMID:11728470
- ↑ Huang TF, Liu CZ, Yang SH. Aggretin, a novel platelet-aggregation inducer from snake (Calloselasma rhodostoma) venom, activates phospholipase C by acting as a glycoprotein Ia/IIa agonist. Biochem J. 1995 Aug 1;309 ( Pt 3):1021-7. PMID:7639679
- ↑ Chung CH, Peng HC, Huang TF. Aggretin, a C-type lectin protein, induces platelet aggregation via integrin alpha(2)beta(1) and GPIb in a phosphatidylinositol 3-kinase independent pathway. Biochem Biophys Res Commun. 2001 Jul 20;285(3):689-95. PMID:11453648 doi:http://dx.doi.org/10.1006/bbrc.2001.5228
- ↑ Bergmeier W, Bouvard D, Eble JA, Mokhtari-Nejad R, Schulte V, Zirngibl H, Brakebusch C, Fassler R, Nieswandt B. Rhodocytin (aggretin) activates platelets lacking alpha(2)beta(1) integrin, glycoprotein VI, and the ligand-binding domain of glycoprotein Ibalpha. J Biol Chem. 2001 Jul 6;276(27):25121-6. Epub 2001 May 14. PMID:11352922 doi:http://dx.doi.org/10.1074/jbc.M103892200
- ↑ Chung CH, Wu WB, Huang TF. Aggretin, a snake venom-derived endothelial integrin alpha 2 beta 1 agonist, induces angiogenesis via expression of vascular endothelial growth factor. Blood. 2004 Mar 15;103(6):2105-13. Epub 2003 Nov 20. PMID:14630793 doi:http://dx.doi.org/10.1182/blood-2003-07-2483
- ↑ Suzuki-Inoue K, Fuller GL, Garcia A, Eble JA, Pohlmann S, Inoue O, Gartner TK, Hughan SC, Pearce AC, Laing GD, Theakston RD, Schweighoffer E, Zitzmann N, Morita T, Tybulewicz VL, Ozaki Y, Watson SP. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood. 2006 Jan 15;107(2):542-9. Epub 2005 Sep 20. PMID:16174766 doi:2005-05-1994
- ↑ Hooley E, Papagrigoriou E, Navdaev A, Pandey AV, Clemetson JM, Clemetson KJ, Emsley J. The crystal structure of the platelet activator aggretin reveals a novel (alphabeta)2 dimeric structure. Biochemistry. 2008 Jul 29;47(30):7831-7. Epub 2008 Jul 3. PMID:18597489 doi:10.1021/bi800528t
|
