| Structural highlights
Disease
[GP1BA_HUMAN] Genetic variations in GP1BA may be a cause of susceptibility to non-arteritic anterior ischemic optic neuropathy (NAION) [MIM:258660]. NAION is an ocular disease due to ischemic injury to the optic nerve. It usually affects the optic disk and leads to visual loss and optic disk swelling of a pallid nature. Visual loss is usually sudden, or over a few days at most and is usually permanent, with some recovery possibly occurring within the first weeks or months. Patients with small disks having smaller or non-existent cups have an anatomical predisposition for non-arteritic anterior ischemic optic neuropathy. As an ischemic episode evolves, the swelling compromises circulation, with a spiral of ischemia resulting in further neuronal damage.[1] Defects in GP1BA are a cause of Bernard-Soulier syndrome (BSS) [MIM:231200]; also known as giant platelet disease (GPD). BSS patients have unusually large platelets and have a clinical bleeding tendency.[2] [3] [4] [5] [6] [7] Defects in GP1BA are the cause of benign mediterranean macrothrombocytopenia (BMM) [MIM:153670]; also known as autosomal dominant benign Bernard-Soulier syndrome. BMM is characterized by mild or no clinical symptoms, normal platelet function, and normal megakaryocyte count.[8] Defects in GP1BA are the cause of pseudo-von Willebrand disease (VWDP) [MIM:177820]. A bleeding disorder is caused by an increased affinity of GP-Ib for soluble vWF resulting in impaired hemostatic function due to the removal of vWF from the circulation.[9] [10] [11] [12]
Function
[GP1BA_HUMAN] GP-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to the A1 domain of vWF, which is already bound to the subendothelium.
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
Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in mediating the arrest of platelets at sites of vascular damage. GPIb binds to the A1 domain of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet adhesion and contributing to the formation of a thrombus. To investigate the molecular basis of GPIb regulation and ligand binding, we have determined the structure of the N-terminal domain of the GPIb(alpha) chain (residues 1-279). This structure is the first determined from the cell adhesion/signaling class of leucine-rich repeat (LRR) proteins and reveals the topology of the characteristic disulfide-bonded flanking regions. The fold consists of an N-terminal beta-hairpin, eight leucine-rich repeats, a disulfide-bonded loop, and a C-terminal anionic region. The structure also demonstrates a novel LRR motif in the form of an M-shaped arrangement of three tandem beta-turns. Negatively charged binding surfaces on the LRR concave face and anionic region indicate two-step binding kinetics to vWF-A1, which can be regulated by an unmasking mechanism involving conformational change of a key loop. Using molecular docking of the GPIb and vWF-A1 crystal structures, we were also able to model the GPIb.vWF-A1 complex.
Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation.,Uff S, Clemetson JM, Harrison T, Clemetson KJ, Emsley J J Biol Chem. 2002 Sep 20;277(38):35657-63. Epub 2002 Jun 26. PMID:12087105[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Salomon O, Rosenberg N, Steinberg DM, Huna-Baron R, Moisseiev J, Dardik R, Goldan O, Kurtz S, Ifrah A, Seligsohn U. Nonarteritic anterior ischemic optic neuropathy is associated with a specific platelet polymorphism located on the glycoprotein Ibalpha gene. Ophthalmology. 2004 Jan;111(1):184-8. PMID:14711733 doi:10.1016/j.ophtha.2003.05.006
- ↑ Miller JL, Lyle VA, Cunningham D. Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ib alpha leucine tandem repeat occurring in patients with an autosomal dominant variant of Bernard-Soulier disease. Blood. 1992 Jan 15;79(2):439-46. PMID:1730088
- ↑ Ware J, Russell SR, Marchese P, Murata M, Mazzucato M, De Marco L, Ruggeri ZM. Point mutation in a leucine-rich repeat of platelet glycoprotein Ib alpha resulting in the Bernard-Soulier syndrome. J Clin Invest. 1993 Sep;92(3):1213-20. PMID:7690774 doi:http://dx.doi.org/10.1172/JCI116692
- ↑ Simsek S, Noris P, Lozano M, Pico M, von dem Borne AE, Ribera A, Gallardo D. Cys209 Ser mutation in the platelet membrane glycoprotein Ib alpha gene is associated with Bernard-Soulier syndrome. Br J Haematol. 1994 Dec;88(4):839-44. PMID:7819107
- ↑ de la Salle C, Baas MJ, Lanza F, Schwartz A, Hanau D, Chevalier J, Gachet C, Briquel ME, Cazenave JP. A three-base deletion removing a leucine residue in a leucine-rich repeat of platelet glycoprotein Ib alpha associated with a variant of Bernard-Soulier syndrome (Nancy I). Br J Haematol. 1995 Feb;89(2):386-96. PMID:7873390
- ↑ Kenny D, Jonsson OG, Morateck PA, Montgomery RR. Naturally occurring mutations in glycoprotein Ibalpha that result in defective ligand binding and synthesis of a truncated protein. Blood. 1998 Jul 1;92(1):175-83. PMID:9639514
- ↑ Koskela S, Partanen J, Salmi TT, Kekomaki R. Molecular characterization of two mutations in platelet glycoprotein (GP) Ib alpha in two Finnish Bernard-Soulier syndrome families. Eur J Haematol. 1999 Mar;62(3):160-8. PMID:10089893
- ↑ Savoia A, Balduini CL, Savino M, Noris P, Del Vecchio M, Perrotta S, Belletti S, Poggi, Iolascon A. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. Blood. 2001 Mar 1;97(5):1330-5. PMID:11222377
- ↑ Matsubara Y, Murata M, Sugita K, Ikeda Y. Identification of a novel point mutation in platelet glycoprotein Ibalpha, Gly to Ser at residue 233, in a Japanese family with platelet-type von Willebrand disease. J Thromb Haemost. 2003 Oct;1(10):2198-205. PMID:14521605
- ↑ Miller JL, Cunningham D, Lyle VA, Finch CN. Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4761-5. PMID:2052556
- ↑ Murata M, Russell SR, Ruggeri ZM, Ware J. Expression of the phenotypic abnormality of platelet-type von Willebrand disease in a recombinant glycoprotein Ib alpha fragment. J Clin Invest. 1993 May;91(5):2133-7. PMID:8486780 doi:http://dx.doi.org/10.1172/JCI116438
- ↑ Russell SD, Roth GJ. Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor. Blood. 1993 Apr 1;81(7):1787-91. PMID:8384898
- ↑ Uff S, Clemetson JM, Harrison T, Clemetson KJ, Emsley J. Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation. J Biol Chem. 2002 Sep 20;277(38):35657-63. Epub 2002 Jun 26. PMID:12087105 doi:10.1074/jbc.M205271200
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