3rez | pdb_00003rez
glycoprotein GPIb variant
Structural highlights
Disease[GP1BB_HUMAN] Bernard-Soulier syndrome;22q11.2 deletion syndrome;Fetal and neonatal alloimmune thrombocytopenia. The disease is caused by mutations affecting the gene represented in this entry. Function[GP1BB_HUMAN] Gp-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to von Willebrand factor, which is already bound to the subendothelium. Publication Abstract from PubMedPlatelet GPIb-IX receptor complex has 3 subunits GPIbalpha, GPIbbeta, and GPIX, which assemble with a ratio of 1:2:1. Dysfunction in surface expression of the complex leads to Bernard-Soulier syndrome. We have crystallized the GPIbbeta ectodomain (GPIbbeta(E)) and determined the structure to show a single leucine-rich repeat with N- and C-terminal disulphide-bonded capping regions. The structure of a chimera of GPIbbeta(E) and 3 loops (a,b,c) taken from the GPIX ectodomain sequence was also determined. The chimera (GPIbbeta(Eabc)), but not GPIbbeta(E), forms a tetramer in the crystal, showing a quaternary interface between GPIbbeta and GPIX. Central to this interface is residue Tyr106 from GPIbbeta, which inserts into a pocket generated by 2 loops (b,c) from GPIX. Mutagenesis studies confirmed this interface as a valid representation of interactions between GPIbbeta and GPIX in the full-length complex. Eight GPIbbeta missense mutations identified from patients with Bernard-Soulier syndrome were examined for changes to GPIb-IX complex surface expression. Two mutations, A108P and P74R, were found to maintain normal secretion/folding of GPIbbeta(E) but were unable to support GPIX surface expression. The close structural proximity of these mutations to Tyr106 and the GPIbbeta(E) interface with GPIX indicates they disrupt the quaternary organization of the GPIb-IX complex. Quaternary organization of GPIb-IX complex and insights into Bernard-Soulier syndrome revealed by the structures of GPIbbeta and a GPIbbeta/GPIX chimera.,McEwan PA, Yang W, Carr KH, Mo X, Zheng X, Li R, Emsley J Blood. 2011 Nov 10;118(19):5292-301. Epub 2011 Sep 8. PMID:21908432[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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