Glycoprotein Ib–IX–V

Andrews, Robert K.; Gardiner, Elizabeth E.; Shen, Yang; Whisstock, James C.; Berndt, Michael C.

doi:10.1016/s1357-2725(02)00280-7

Cited by 193 publications

(186 citation statements)

References 14 publications

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“…The ␣-subunit of GP Ib (GP Ib␣) contains all of the known ligand-binding sites within the complex with the other subunits necessary for efficient surface expression of the complex. 9,10 Mutations within the GP Ib␣ gene most commonly associated with Pt-vWD result in an amino acid change at position 233 (G233V or G233S) or position 239 (M239V). 6,11,12 One report describes a 27-bp deletion within the GP Ib␣ macroglycopeptide domain that results in a Pt-vWD phenotype.…”

mentioning

confidence: 99%

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Suva

Hartman

Dilley

et al. 2008

The American Journal of Pathology

110

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The platelet glycoprotein Ib-IX receptor binds surfacebound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass. (Am J

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mentioning

confidence: 99%

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Suva

Hartman

Dilley

et al. 2008

The American Journal of Pathology

110

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“…1 Once the vWF ligand binds to the extracellular domain of Iba, the GP Ib-IX-V complex transmits a signal across the membrane that activates intracellular effectors and stimulates integrin a IIb b 3 , leading to platelet activation and aggregation. 2,3 Malfunction of this multisubunit receptor complex can lead to severe bleeding diathesis and contribute to many cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

The dimerization interface of the glycoprotein Ibβ transmembrane domain corresponds to polar residues within a leucine zipper motif

Wei

Liu

et al. 2011

Protein Science

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Experiments with the transmembrane (TM) domains of the glycoprotein (GP) Ib-IX complex have indicated that the associations between the TM domains of these subunits play an important role in the proper assembly of the complex. As a first step toward understanding these associations, we previously found that the Ibb TM domain dimerized strongly in Escherichia coli cell membranes and led to Ibb TM-CYTO (cytoplasmic domain) dimerization in the SDS-PAGE assay, while neither Iba nor IX TM-CYTO was able to dimerize. In this study, we used the TOXCAT assay to probe the Ibb TM domain dimerization interface by Ala-and Leu-scanning mutagenesis. Our results show that this interface is based on a leucine zipper-like heptad repeat pattern of amino acids. Mutating either one of polar residues Gln129 or His139 to Leu or Ala disrupted Ibb TM dimerization dramatically, indicating that polar residues might form part of the leucine zipperbased dimerization interface. Furthermore, these specific mutational effects in the TOXCAT assay were confirmed in the thiol-disulfide exchange and SDS-PAGE assays. The computational modeling studies further revealed that the most likely leucine zipper interface involves hydrogen bonding of Gln129 and electrostatic interaction of the His139 side chain. Correlation of computer modeling results with experimental mutagenesis studies on the Ibb TM domain may provide insights for understanding the role of the association of TM domains on the assembly of GP Ib-IX complex.

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Section: Leucine-rich Repeat Proteinsmentioning

confidence: 99%

“…Its major function is initiating thrombus formation at high shear stress in flowing blood (Andrews 2003). It binds to vWF in the subendothelial matrix or plasma, as well as Mac-1 on neutrophils and Pselectin on activated platelets and endothelial cells (Andrews 2003). Its absence or dysfunction leads to Bernard-Soulier syndrome, a rare but often severe bleeding disorder (Andrews 1997, Lopez 1998).…”

Section: Leucine-rich Repeat Proteinsmentioning

confidence: 99%

“…Following binding, platelets become activated, leading to shape change, spreading, and granule secretion caused by cytoskeletal rearrangement, recruiting additional platelets to the developing thrombus. GPIb-IX-V signal transduction, involving PI-3-kinase, Syk, Src, and ERK-1/2, leads to activation of GPIIb-IIIa, mediating platelet aggregation (Andrews 2003.…”

Section: Leucine-rich Repeat Proteinsmentioning

confidence: 99%

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The Tetraspanin CD9 Localizes to Platelet-Platelet Contacts and Regulates Thrombus Stability

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Glycoprotein Ib–IX–V

Cited by 193 publications

References 14 publications

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

The dimerization interface of the glycoprotein Ibβ transmembrane domain corresponds to polar residues within a leucine zipper motif

The Tetraspanin CD9 Localizes to Platelet-Platelet Contacts and Regulates Thrombus Stability

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