Alternative titles; symbols
HGNC Approved Gene Symbol: GP5
Cytogenetic location: 3q29 Genomic coordinates (GRCh38): 3:194,394,821-194,399,266 (from NCBI)
Human platelet glycoprotein V (GP5) is a part of the Ib-V-IX system of surface glycoproteins that constitute the receptor for von Willebrand factor (VWF; 613160) and mediate the adhesion of platelets to injured vascular surfaces in the arterial circulation, a critical initiating event in hemostasis. The main portion of the receptor is a heterodimer composed of 2 polypeptide chains, an alpha chain (GP1BA; 606672) and a beta chain (GP1BB; 138720), that are linked by disulfide bonds. The complete receptor complex includes noncovalent association of the alpha and beta subunits with platelet glycoprotein IX (GP9; 173515) and GP5. Mutations in GP1BA, GP1BB, and GP9 have been shown to cause Bernard-Soulier syndrome (BSS; 231200), a bleeding disorder (review by Lopez et al., 1998).
Using PCR techniques and platelet cDNA templates, Hickey et al. (1993) obtained l.4 kb of GP V cDNA sequence encoding 469 amino acids of the polypeptide. Northern blot analysis revealed 3 GP V platelet transcripts of 3.8, 4.2, and 5.2 kb. A 16-amino acid signal peptide was present. The mature GP V is a 544-amino acid transmembrane protein with a 504-amino acid extracellular domain and a total molecular mass of 82 kD.
Lanza et al. (1993) cloned and sequenced the GP V gene. Northern blot analysis identified a single transcript of 4.5 kb in human platelets. The protein contains a single transmembrane domain, a short cytoplasmic domain, and a large extracellular domain with 8 potential N-glycosylation sites. Analysis of the extracellular domain of the protein revealed the presence of 15 tandem leucine-rich repeats of 24 amino acids, similar to the other 3 proteins of the GP Ib receptor complex. Lanza et al. (1993) also identified a cleavage site for thrombin near the C terminus with similarity to the A alpha chain of fibrinogen (134820). RT-PCR analysis on RNAs from cells of different hematopoietic origins revealed that GP V was specifically transcribed from platelets and from cells of the megakaryocytic lineage.
Hickey et al. (1993) and Lanza et al. (1993) determined that the coding sequence of the GP5 gene is contained within a single exon. Yagi et al. (1995) stated that the GP5 gene contains 2 exons, the first consisting of approximately 37 bases and the second of approximately 3,500 bases, interrupted by a single 958-base intron.
By fluorescence in situ hybridization, Yagi et al. (1995) mapped the GP5 gene to chromosome 3q29.
Calverley et al. (1995) studied the role of the GP V subunit within the GP Ib receptor complex by transfecting the GP5 gene into a hematopoietic cell line that constitutively expresses the other 3 subunits. Using flow cytometry, they found that transfected GP5 was expressed on the surface of these human erythroleukemia (HEL) cells; this in turn led to increased surface expression of the ligand-binding GP Ib-alpha and GP IX subunits. Radioligand binding assays showed that GP5-transfected HEL cells bound more VWF than their non- or mock-transfected counterparts. With confocal microscopy of GP5-transfected HEL cells, they showed that GP V colocalizes with GP Ib-alpha on the cell surface. These findings suggested that the GP V subunit plays a role within the GP Ib receptor complex by enhancing Ib-alpha surface expression.
By investigating 38 rheumatoid arthritis patients on gold therapy, 10 with profound thrombocytopenia and 28 nonthrombocytopenic controls, Garner et al. (2002) showed that in all 10 patients with thrombocytopenia, the platelet autoantibodies preferentially targeted GP V, although the presence of gold was not required for their reactivity. The authors showed the GP V specificity of the platelet-associated IgG, which was elevated in 8 of the 10 patients. Thus, GP V seemed to be targeted in gold-induced autoimmune thrombocytopenia.
GP V is the major thrombin substrate on intact platelets cleaved during thrombin-induced platelet aggregation, and promotes GP Ib-IX surface expression in heterologous cells. In GP V null mice, Ramakrishnan et al. (1999) tested the hypotheses that GP V is involved in thrombin-induced platelet activation, in GP Ib-IX expression, and in other platelet responses. Contrary to expectations, GP V -/- platelets were normal in size and expressed normal amounts of GP Ib-IX that was functional in von Willebrand factor binding, explaining why defects in GP V had not been observed in Bernard-Soulier syndrome, a bleeding disorder caused by a lack of functional GP Ib-IX-V. Moreover, in vitro analysis demonstrated that GP V -/- platelets were hyperresponsive to thrombin, resulting in increased fibrinogen binding and an increased aggregation response. Consistent with these findings, GP V -/- mice had a shorter bleeding time. These data supported a role for GP V as a negative modulator of platelet activation. Furthermore, they suggested a new mechanism by which thrombin enhances platelet responsiveness independent of activation of the classic G protein-coupled thrombin receptors.
To address the role of GP V in vivo, Kahn et al. (1999) generated GP V-deficient mice by gene targeting. GP V-null mice developed normally and exhibited no spontaneous bleeding. GP V-null platelets were normal in size and shape, responded normally to thrombin, and exhibited wildtype adhesion to mouse VWF A1 domain under shear. The results suggested that loss of function in the GP5 gene is unlikely to be a cause of human BSS. Whether redundancy accounted for the lack of phenotype of GP V deficiency, or whether GP V serves subtle or as yet unprobed functions in platelets or other cells, remained to be determined.
Calverley, D. C., Yagi, M., Stray, S. M., Roth, G. J. Human platelet glycoprotein V: its role in enhancing expression of the glycoprotein Ib receptor. Blood 86: 1361-1367, 1995. [PubMed: 7632943]
Garner, S. F., Campbell, K., Metcalfe, P., Keidan, J., Huiskes, E., Dong, J.-F., Lopez, J. A., Ouwehand, W. H. Glycoprotein V: the predominant target antigen in gold-induced autoimmune thrombocytopenia. Blood 100: 344-346, 2002. [PubMed: 12070047] [Full Text: https://doi.org/10.1182/blood.v100.1.344]
Hickey, M. J., Hagen, F. S., Yagi, M., Roth, G. J. Human platelet glycoprotein V: characterization of the polypeptide and the related Ib-V-IX receptor system of adhesive, leucine-rich glycoproteins. Proc. Nat. Acad. Sci. 90: 8327-8331, 1993. [PubMed: 7690959] [Full Text: https://doi.org/10.1073/pnas.90.18.8327]
Kahn, M. L., Diacovo, T. G., Bainton, D. F., Lanza, F., Trejo, J., Coughlin, S. R. Glycoprotein V-deficient platelets have undiminished thrombin responsiveness and do not exhibit a Bernard-Soulier phenotype. Blood 94: 4112-4121, 1999. [PubMed: 10590056]
Lanza, F., Morales, M., de La Salle, C., Cazenave, J.-P., Clemetson, K. J., Shimomura, T., Phillips, D. R. Cloning and characterization of the gene encoding the human platelet glycoprotein V: a member of the leucine-rich glycoprotein family cleaved during thrombin-induced platelet activation. J. Biol. Chem. 268: 20801-20807, 1993. [PubMed: 8407908]
Lopez, J. A., Andrews, R. K., Afshar-Kharghan, V., Berndt, M. C. Bernard-Soulier syndrome. Blood 91: 4397-4418, 1998. [PubMed: 9616133]
Ramakrishnan, V., Reeves, P. S., DeGuzman, F., Deshpande, U., Ministri-Madrid, K., DuBridge, R. B., Phillips, D. R. Increased thrombin responsiveness in platelets from mice lacking glycoprotein V. Proc. Nat. Acad. Sci. 96: 13336-13341, 1999. [PubMed: 10557321] [Full Text: https://doi.org/10.1073/pnas.96.23.13336]
Yagi, M., Edelhoff, S., Disteche, C. M., Roth, G. J. Human platelet glycoproteins V and IX: mapping of two leucine-rich glycoprotein genes to chromosome 3 and analysis of structures. Biochemistry 34: 16132-16137, 1995. [PubMed: 8519770] [Full Text: https://doi.org/10.1021/bi00049a028]