Surface expression of glycoprotein Ibα is dependent on glycoprotein Ibβ: evidence from a novel mutation causing Bernard-Soulier syndrome

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 532-539 ◽  
Author(s):  
Niamh Moran ◽  
Patricia A. Morateck ◽  
Adele Deering ◽  
Michelle Ryan ◽  
Robert R. Montgomery ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Chinese Hamster ◽  
Surface Expression ◽  
Confocal Imaging ◽  
Stable Cell Line ◽  
Platelet Glycoprotein ◽  
Gene Encoding ◽  
Platelet Surface ◽  
Platelet Receptor ◽  
Bernard Soulier Syndrome

Abstract Bernard-Soulier syndrome is a rare bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP) Ib-IX-V complex. The complex, which serves as a platelet receptor for von Willebrand factor, is composed of 4 subunits: GPIb, GPIbβ, GPIX, and GPV. We here describe the molecular basis of a novel form of Bernard-Soulier syndrome in a patient in whom the components of the GPIb-IX-V complex were undetectable on the platelet surface. Although confocal imaging confirmed that GPIb was not present on the platelet surface, GPIb was readily detectable in the patient's platelets. Moreover, immunoprecipitation of plasma with specific monoclonal antibodies identified circulating, soluble GPIb. DNA-sequence analysis revealed normal sequences for GPIb and GPIX. There was a G to A substitution at position 159 of the gene encoding GPIbβ, resulting in a premature termination of translation at amino acid 21. Studies of transient coexpression of this mutant, W21stop-GPIbβ, together with wild-type GPIb and GPIX, demonstrated a failure of GPIX expression on the surface of HEK 293T cells. Similar results were obtained with Chinese hamster ovary  IX cells, a stable cell line expressing GPIb that retains the capacity to re-express GPIX. Thus, we found that GPIbβ affects the surface expression of the GPIb-IX complex by failing to support the insertion of GPIb and GPIX into the platelet membrane.

Surface expression of glycoprotein Ibα is dependent on glycoprotein Ibβ: evidence from a novel mutation causing Bernard-Soulier syndrome

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 532-539 ◽  
Author(s):  
Niamh Moran ◽  
Patricia A. Morateck ◽  
Adele Deering ◽  
Michelle Ryan ◽  
Robert R. Montgomery ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Chinese Hamster ◽  
Surface Expression ◽  
Confocal Imaging ◽  
Stable Cell Line ◽  
Platelet Glycoprotein ◽  
Gene Encoding ◽  
Platelet Surface ◽  
Platelet Receptor ◽  
Bernard Soulier Syndrome

Bernard-Soulier syndrome is a rare bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP) Ib-IX-V complex. The complex, which serves as a platelet receptor for von Willebrand factor, is composed of 4 subunits: GPIb, GPIbβ, GPIX, and GPV. We here describe the molecular basis of a novel form of Bernard-Soulier syndrome in a patient in whom the components of the GPIb-IX-V complex were undetectable on the platelet surface. Although confocal imaging confirmed that GPIb was not present on the platelet surface, GPIb was readily detectable in the patient's platelets. Moreover, immunoprecipitation of plasma with specific monoclonal antibodies identified circulating, soluble GPIb. DNA-sequence analysis revealed normal sequences for GPIb and GPIX. There was a G to A substitution at position 159 of the gene encoding GPIbβ, resulting in a premature termination of translation at amino acid 21. Studies of transient coexpression of this mutant, W21stop-GPIbβ, together with wild-type GPIb and GPIX, demonstrated a failure of GPIX expression on the surface of HEK 293T cells. Similar results were obtained with Chinese hamster ovary  IX cells, a stable cell line expressing GPIb that retains the capacity to re-express GPIX. Thus, we found that GPIbβ affects the surface expression of the GPIb-IX complex by failing to support the insertion of GPIb and GPIX into the platelet membrane.

Differential Pathogenesis of Bernard-Soulier Syndrome-Associated Mutations In the Platelet Glycoprotein Ibβ Ectodomain

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3202-3202
Author(s):  
Wenjun Yang ◽  
P.A McEwan ◽  
Xi Mo ◽  
Jonas Emsley ◽  
Renhao Li
Keyword(s):  
Cho Cells ◽  
Disulfide Bonds ◽  
Surface Expression ◽  
Full Length ◽  
Platelet Glycoprotein ◽  
Interfacial Region ◽  
Support Surface ◽  
Wild Type ◽  
Platelet Surface ◽  
Bernard Soulier Syndrome

Abstract Abstract 3202 Eight missense mutations in the ectodomain of glycoprotein (GP)Ibβ have been identified in patients with Bernard-Soulier syndrome (BSS) that is characterized by the deficiency of functional GPIb-IX complex on the platelet surface, clearly highlighting the importance of GPIbβ ectodomain in assembly of the GPIb-IX complex. To understand the molecular pathogenesis of these mutations, we have characterized their effects on the expression, secretion, folding of the isolated GPIbβ ectodomain as well as its interaction with GPIX ectodomain in the context of full-length complex. Each of the 8 mutations — C5Y, R17C, P29L, N64T, P74R, Y88C, P96S, and A108P — was constructed into genes encoding HA-tagged GPIbβ ectodomain or full-length GPIbβ subunit, and the mutant gene transfected transiently, along with GPIba and GPIX genes if desired, into Chinese hamster ovary (CHO) cells. Flow cytometry and Western blot analysis indicated that while all 8 mutations impeded formation of the disulfide bonds between GPIba and GPIbβ and significantly decreased the surface expression level of GPIb-IX complex comparing to the wild-type, the extent of disruption varies with each mutation. Further characterization in the context of isolated GPIbβ ectodomain revealed that the majority of 8 mutations — C5Y, R17C, P29L, N64T, Y88C, P96S — are detrimental to proper folding of the GPIbβ ectodomain, resulting in secretion defects and/or domain misfolding. In contrast, two mutations, P74R and A108P, preserved structural integrity of the GPIbβ ectodomain since the mutant ectodomains exhibited wild-type-like secretion levels and formed no inter-molecular disulfide bonds. However, neither of the two mutations, in the context of full-length GPIbβ, were able to support surface expression of GPIX in transfected CHO cells as the wild-type, indicating that P74R and A108P disrupt the interaction between GPIbβ and GPIX ectodomains. Thus, our results demonstrated although all 8 BSS mutations in GPIbβ share the same phenotype, they impair expression of the GPIb-IX complex by two different mechanisms — disrupting folding of the GPIbβ ectodomain or disrupting interactions between GPIb-IX subunits. Furthermore, our results suggest that Pro74 and Ala108 may be located in the interfacial region between GPIbβ and GPIX ectodomains, helping to shed light on the structure of GPIb-IX complex. Disclosures: No relevant conflicts of interest to declare.

A novel mutation in the transmembrane region of glycoprotein IX associated with Bernard-Soulier syndrome

2004 ◽  
Vol 92 (09) ◽  
pp. 606-613 ◽  
Author(s):  
Xiaojuan Zhao ◽  
Weiming Duan ◽  
Jianxin Fu ◽  
Mingen Lu ◽  
Giamin Wang ◽  
...  
Keyword(s):  
Cho Cells ◽  
Novel Mutation ◽  
Flow Cytometric Analysis ◽  
Chinese Hamster ◽  
Surface Expression ◽  
Enzyme Analysis ◽  
Restriction Enzyme Analysis ◽  
Wild Type ◽  
Transmembrane Region ◽  
Bernard Soulier Syndrome

SummaryWe describe here a novel mutation in glycoprotein (GP) IX transmembrane region in a patient with Bernard-Soulier syndrome (BSS). Flow cytometric analysis of the patient’s platelets showed that GP Iba and GP IX were expressed at decreased levels. Sequence analysis of the gene coding for GP IX revealed a homozygous (G to A) transition at nucleotide 2113, resulting in a Ala 140 (GCC) to Thr (ACC) replacement in the mature peptide, whereas no defects were found in the coding region of the GP Iba and GP Ib? gene. Allele-specific restriction enzyme analysis using HPYCH4 III revealed that the patient was homozygous and her mother and brother were heterozygous for the defect, and excluded the possibility that the mutation was a polymorphism of GP IX.To clarify the effect of this mutation on the surface expression of the GP Ib/IX complex, we introduced this mutation into the cDNA of GP IX by site-directed mutagenesis and performed in vitro transfection studies with plasmids harboring GP Iba, GP Ib? and wild-type GP IX or mutant GP IX. Mutant GP IX decreased the surface expression of GP Iba and GP IX, whereas both immunostaining and immunoblotting of the transfected Chinese hamster ovary (CHO) cells showed abundant GP Iba and GP IX in the cytoplasm of the CHO cells transfected with plasmids harboring GP Iba, GP Ib? and wild-type GP IX or mutant GP IX These findings indicate that the Ala140→Thr mutation in the transmembrane region of GP IX does not induce intracellular GP Ib/IX complex degradation, but prevents its insertion in the cytoplasmic membrane of platelets and CHO cells.

The Critical Interaction of Glycoprotein (GP) Ibβ With GPIX—A Genetic Cause of Bernard-Soulier Syndrome

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2968-2975 ◽  
Author(s):  
Dermot Kenny ◽  
Patricia A. Morateck ◽  
Joan C. Gill ◽  
Robert R. Montgomery
Keyword(s):  
Amino Acids ◽  
Chinese Hamster Ovary Cells ◽  
Surface Expression ◽  
Platelet Glycoprotein ◽  
Wild Type ◽  
Single Nucleotide ◽  
Platelet Surface ◽  
Single Nucleotide Deletion ◽  
Nucleotide Deletion ◽  
Bernard Soulier Syndrome

Bernard-Soulier syndrome is an uncommon bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP)Ib/IX complex. The complex is composed of four subunits, GPIb, GPIbβ, GPIX, and GPV. Here we describe the molecular basis of a novel Bernard-Soulier syndrome variant in a patient in whom GPIb and GPIX were undetectable on the platelet surface. DNA sequence analysis showed normal sequence for GPIb, GPIX, and GPV. The GPIbβ gene has been mapped to the 22q11.2 region of chromosome 22 which was deleted from one chromosome of this patient. There was a single nucleotide deletion within the codon for Ala 80 in GPIbβ within the other allele. This mutation causes a translational frame shift that encodes for 86 altered amino acids and predicts a premature stop 15 amino acids short of the length of the wild-type protein. Transient coexpression of the mutant GPIbβ in 293T cells with wild-type GPIb and GPIX resulted in the surface expression of GPIb, but the absence of GPIX. Moreover, when a plasmid encoding the wild-type GPIbβ was transiently transfected into Chinese hamster ovary cells stably expressing GP, which retain the capacity to reexpress GPIX, there was a significant increase in the surface expression of GPIX. In contrast, when the mutant GPIbβ was transiently transfected into these cells, GPIX was not reexpressed on the plasma surface. Thus, a deletion of one copy of GPIbβ and a single nucleotide deletion in the codon for Ala 80 within the remaining GPIbβ allele causes the Bernard-Soulier phenotype through an interaction of GPIbβ with GPIX resulting in the absence of GPIb on the plasma membrane. The interaction of GPIbβ with GPIX is essential for the functional expression of GPIb.

The Critical Interaction of Glycoprotein (GP) Ibβ With GPIX—A Genetic Cause of Bernard-Soulier Syndrome

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2968-2975 ◽  
Author(s):  
Dermot Kenny ◽  
Patricia A. Morateck ◽  
Joan C. Gill ◽  
Robert R. Montgomery
Keyword(s):  
Amino Acids ◽  
Chinese Hamster Ovary Cells ◽  
Surface Expression ◽  
Platelet Glycoprotein ◽  
Wild Type ◽  
Single Nucleotide ◽  
Platelet Surface ◽  
Single Nucleotide Deletion ◽  
Nucleotide Deletion ◽  
Bernard Soulier Syndrome

Abstract Bernard-Soulier syndrome is an uncommon bleeding disorder caused by a quantitative or qualitative defect in the platelet glycoprotein (GP)Ib/IX complex. The complex is composed of four subunits, GPIb, GPIbβ, GPIX, and GPV. Here we describe the molecular basis of a novel Bernard-Soulier syndrome variant in a patient in whom GPIb and GPIX were undetectable on the platelet surface. DNA sequence analysis showed normal sequence for GPIb, GPIX, and GPV. The GPIbβ gene has been mapped to the 22q11.2 region of chromosome 22 which was deleted from one chromosome of this patient. There was a single nucleotide deletion within the codon for Ala 80 in GPIbβ within the other allele. This mutation causes a translational frame shift that encodes for 86 altered amino acids and predicts a premature stop 15 amino acids short of the length of the wild-type protein. Transient coexpression of the mutant GPIbβ in 293T cells with wild-type GPIb and GPIX resulted in the surface expression of GPIb, but the absence of GPIX. Moreover, when a plasmid encoding the wild-type GPIbβ was transiently transfected into Chinese hamster ovary cells stably expressing GP, which retain the capacity to reexpress GPIX, there was a significant increase in the surface expression of GPIX. In contrast, when the mutant GPIbβ was transiently transfected into these cells, GPIX was not reexpressed on the plasma surface. Thus, a deletion of one copy of GPIbβ and a single nucleotide deletion in the codon for Ala 80 within the remaining GPIbβ allele causes the Bernard-Soulier phenotype through an interaction of GPIbβ with GPIX resulting in the absence of GPIb on the plasma membrane. The interaction of GPIbβ with GPIX is essential for the functional expression of GPIb.

Quaternary Organization of GPIb-IX Complex and Insights Into Bernard-Soulier Syndrome Revealed by the Crystal Structures of GPIbβ Ectodomain and a GPIbβ/GPIX Chimera

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2195-2195
Author(s):  
Paul A. McEwan ◽  
Wenjun Yang ◽  
Katherine H. Carr ◽  
Xi Mo ◽  
Xiaofeng Zheng ◽  
...  
Keyword(s):  
Structural Model ◽  
Conflicts Of Interest ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Complex Surface ◽  
Surface Expression ◽  
Platelet Glycoprotein ◽  
Missense Mutations ◽  
Ovary Cells ◽  
Bernard Soulier Syndrome

Abstract Abstract 2195 Platelet glycoprotein (GP)Ib-IX receptor complex contains three subunits, GPIbα, GPIbβ and GPIX, which assemble with a ratio of 1:2:1. Dysfunction in surface expression of the complex leads to Bernard-Soulier syndrome (BSS). We have crystallized the GPIbβ ectodomain (GPIbβE) and determined the structure to reveal a single leucine-rich repeat with N- and C-terminal disulfide bonded capping regions. The central region of the structure can be divided into concave parallel β-sheet and convex loops. The crystal structure of a GPIbβE/GPIXE chimera that contains three non-continguous convex loops of GPIX and retains a GPIbβ-binding site of GPIX (Mo et al. J. Thromb. Haemost. 7:1533–40, 2009) was also determined. The chimera, but not GPIbβE, forms a homotetramer in the crystal, revealing a quaternary interface between GPIbβ and GPIX ectodomains. Central to this interface is residue Tyr106 from GPIbβ that inserts into a shallow and largely hydrophobic pocket generated by two convex loops from GPIX. Mutagenesis studies confirmed this interface as a valid representation of interactions between GPIbβ and GPIX in the full-length complex. Eight GPIbβ missense mutations identified from BSS patients were examined in transiently transfected Chinese hamster ovary cells for changes to the GPIb-IX complex surface expression. Six of the eight mutations lead to secretion defect and/or misfolding of GPIbβE. In contrast, the other two mutations, A108P and P74R, were found to maintain normal secretion and folding of GPIbβE but were unable to support GPIX surface expression. The close structural proximity of these mutations to Tyr106 and the GPIbβE interface with GPIX indicates that residues Ala108 and Pro74 in GPIbβ are located at the GPIbβE/GPIXE interfaces. Based on the tetrameric arrangement of the chimera structure, we propose a structural model for the GPIb-IX complex that embodies its organizing principles and helps to provide mechanistic insights on its assembly, function and regulation. Disclosures: No relevant conflicts of interest to declare.

A Novel Missense Mutation Asp69Gly in the Platelet Glycoprotein Ib(beta) Gene in Two Families with Bernard-Soulier Syndrome,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3300-3300
Author(s):  
Wolf A Hassenpflug ◽  
Belinda Weber ◽  
Tobias Obser ◽  
Ulrich Budde ◽  
Reinhard Schneppenheim
Keyword(s):  
Surface Expression ◽  
Cell Surface Expression ◽  
Platelet Glycoprotein ◽  
Facs Analysis ◽  
Platelet Surface ◽  
Minimal Trauma ◽  
Recurrent Epistaxis ◽  
The Impact ◽  
Beta Gene ◽  
Bernard Soulier Syndrome

Abstract Abstract 3300 Bernard-Soulier Syndrome (BSS) is characterized by macrothrombocytopenia and impaired platelet function due to defects of the GpIb-IX-V complex. Patients with Bernard-Soulier Syndrome are rare and only few disease causing mutations have been identified in the platelet gylcoprotein Ib(alpha), Ib(beta) or glycoprotein IX genes, respectively. We characterized 2 independent families with Bernard-Soulier Syndrome. Affected members of both families presented with a bleeding history including gross hematoma after minimal trauma, recurrent epistaxis, menorrhagia and prolonged bleeding after surgery. Routine laboratory tests showed reduced platelet numbers and increased platelet volume. Consistent with the diagnosis of Bernard-Soulier syndrome FACS analysis demonstrated reduced GpIb-IX expression on the platelet surface. Platelet agglutination in the presence of ristocetin (RIPA) was impaired. Using standard techniques we sequenced the GpIb(alpha), GpIb(beta) and GpIX genes. We identified a novel mutation Asp69Gly in the GpIb(beta) gene in both families. The mutation was homozygous in two children of the first family and one child of the second family. As expected, the parents of the affected index patients were heterozygous mutation carriers. To further investigate the impact of the Asp69Gly mutation on GpIb expression we used structure prediction software and homology-based protein modeling. Asp69Gly lies within an extracellular region flanking a leucin-rich element and cysteine-cluster. It affects the highly conserved center aspartic acid of a CDC motif that is thought to form one of two cystein-loops close to the transmembrane domain. We propose that this mutation disrupts the regular conformation of the cystein loop, potentially leading to abnormal protein folding and protein decay in the endoplasmic reticulum. In addition to a mere defect of biosynthesis our data hint at additional functional consequences of the Asp69Gly mutation. The father and the mother of the index patient in the first family, who are heterzygous for the Asp69Gly mutation, express only slightly reduced levels of platelet GpIb-IX based on FACS analysis. Nevertheless both of them suffer from epistaxis and menorrhagia, respectively. Expression studies are underway to clarify the influence of the Asp69Gly mutation on GpIb expression and function. Preliminary data show reduced cell surface expression of the GPIb-IX complex and reduced binding to von Willebrand-factor (VWF). While the functional and structural effects of mutations in the GpIb(alpha) and GpIX genes have been thoroughly studied, the impact of mutations in the GpIb(beta) gene is less clear. Our results could help to elucidate how the GpIb(beta) protein contributes to the assembly and surface expression of the GpIb-IX-V complex. Disclosures: No relevant conflicts of interest to declare.

Homozygous Pro74 → Arg Mutation in the Platelet Glycoprotein Ibβ Gene Associated with Bernard-Soulier Syndrome

2000 ◽  
Vol 84 (07) ◽  
pp. 112-117 ◽  
Author(s):  
Yoshiaki Tomiyama ◽  
Shigenori Honda ◽  
Mariko Fukunishi ◽  
Junichi Hara ◽  
Chikako Inoue ◽  
...  
Keyword(s):  
Restriction Analysis ◽  
Flow Cytometric Analysis ◽  
Immunoblot Analysis ◽  
Surface Expression ◽  
Platelet Glycoprotein ◽  
Sequencing Analysis ◽  
Platelet Receptor ◽  
Dna Sequencing Analysis ◽  
Von Willebrand ◽  
Bernard Soulier Syndrome

SummaryBernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder due to quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von Willebrand factor. This complex is composed of four subunits, GPIbα, GPIbβ, GPIX and GPV. We describe here the genetic basis of the disorder in a patient with BSS. Flow cytometric analysis of the patient’s platelets showed greatly reduced GPIbα and GPIX surface expression. Immunoblot analysis disclosed absence of GPIbα, GPIbβ and GPIX in the platelets. DNA sequencing analysis revealed a novel missense mutation in the GPIbβ gene that converts Pro (CCG) to Arg (CGG) at residue 74. Homozygosity of the mutation was confirmed by allele-specific restriction analysis, chromosome 22 microsatellite analysis and quantitative Southern blotting. The mutant GPIbβ was normally transcribed. Transient transfection studies confirmed that mutant GPIbβ impairs surface expression of GPIb/IX, showing that the mutation is responsible for a BSS phenotype observed in the patient.

Autoantibodies to αIIbβ3 in patients with chronic immune thrombocytopenic purpura bind primarily to epitopes on αIIb

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 2171-2172 ◽  
Author(s):  
Robert McMillan ◽  
Jennifer Lopez-Dee ◽  
Joseph C. Loftus
Keyword(s):  
Immune Thrombocytopenic Purpura ◽  
Cho Cells ◽  
Chinese Hamster ◽  
Surface Proteins ◽  
Platelet Glycoprotein ◽  
Beta Chain ◽  
Platelet Destruction ◽  
Thrombocytopenic Purpura ◽  
Platelet Surface ◽  
Chronic Immune Thrombocytopenic Purpura

Abstract Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease caused by platelet destruction resulting from autoantibodies against platelet surface proteins, particularly platelet glycoprotein IIb/IIIa (αIIbβ3). To localize the auto-epitopes on platelet αIIbβ3, the binding of autoantibodies to Chinese hamster ovary (CHO) cells expressing either αIIbβ3 or αvβ3was studied. Thirteen of 14 ITP autoantibodies bound only to CHO cells expressing αIIbβ3. Because these 2 integrins have the same beta chain (β3), these results show that most epitopes in chronic ITP are dependent on the presence of glycoprotein αIIb.

Role of the α-subunit326GRV sequence in the surface expression of fibrinogen and vitronectin receptors

1998 ◽  
Vol 275 (5) ◽  
pp. C1239-C1246 ◽  
Author(s):  
Milagros Ferrer ◽  
Matilde S. Ayuso ◽  
Nora Butta ◽  
Roberto Parrilla ◽  
Consuelo González-Manchón
Keyword(s):  
Functional Role ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Surface Expression ◽  
Platelet Surface ◽  
Α Subunit ◽  
Vitronectin Receptor ◽  
Ovary Cells ◽  
High Affinity

The platelet GPIIb-GPIIIa heterodimer (integrin αIIbβ3) binds fibrinogen with high affinity in response to activation by agonists, leading to platelet aggregation and formation of a hemostatic plug. The326GRV motif in GPIIb is highly conserved in the α-subunit of other integrins, suggesting that it might play an important functional role. Moreover, Arg327→His substitution in GPIIb has been associated with defective platelet surface expression of GPIIb-IIIa and thrombasthenic phenotype. This work aimed at elucidating whether the absence of Arg327or its substitution by His was responsible for the impaired surface expression of GPIIb-IIIa complexes. Transfection of cDNA encoding [Ala327]GPIIb, [Gln327]GPIIb, or [Phe327]GPIIb into Chinese hamster ovary cells inherently expressing GPIIIa permitted surface exposure of GPIIb-IIIa complexes, whereas [Glu327]GPIIb did not. These observations indicate that it is not the loss of [Arg327]GPIIb but the presence of His327or a negatively charged residue like Glu at position 327 of GPIIb that prevents the surface exposure of GPIIb-IIIa heterodimers. In contrast, changing Gln344, the homologue to Arg327in the α-subunit of the vitronectin receptor, to His did not prevent the surface expression of αv-GPIIIa complexes. Thus the conformational constraint imposed by His327seems to be rather specific for the heterodimerization and/or processing of GPIIb-IIIa complexes.

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