Structures of Glycoprotein Ibα and Its Complex with von Willebrand Factor A1 Domain

Huizinga, Eric G.; Tsuji, Shizuko; Romijn, Roland A.; Schiphorst, Marion E.; Groot, Philip G. de; Sixma, Jan J.; Gros, Piet

doi:10.1126/science.107355

Cited by 527 publications

(601 citation statements)

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“…Mutations affecting a leucine-rich domain of GPIX or its amino-and carboxy-terminal flanking regions all give rise to decreased GPIb/IX/V surface expression on platelets, suggesting that these regions are important to ensure the correct assembly and the stability of the complex [21]. The sequences flanking the LRM of GPIbb, GPIX, and GPIba are very similar, these regions showing conserved cysteine residues that form disulfide loops within the polypeptide, as observed in GPIba by crystallography [22]. It has been suggested that GPIX gene mutations affecting cysteine residues [13,14,21] prevent the formation of intramolecular disulfide-loop structures that are critical for the interaction of the polypeptide with the GPIbb subunit.…”

Section: Discussionmentioning

confidence: 83%

Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome

2004

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Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient. Am.

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Section: Discussionmentioning

confidence: 83%

Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome

2004

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“…A. Based on homology modeling with the structures of the Nogo receptor (He et al, 2003) and glycoprotein Ibα (Huizinga et al, 2002) as outlined in the text. B.…”

Section: Discussionmentioning

confidence: 99%

“…Predicted and experimental structures of the FSHR-ECD N-terminal fragment (residues 1 -241). A. Molecular modeling with the Nogo receptor (He et al, 2003) and glycoprotein Ibα (Huizinga et al, 2002) as templates. B.…”

Section: Discussionmentioning

confidence: 99%

“…The amino acid sequence was first analyzed by PSI-BLAST in order to identify conserved amino acid residues in different species, the sequence profile then being included in the threading. Significant z-scores were obtained with two proteins, glycoprotein Ibα (Huizinga et al, 2002) and the Nogo receptor (He et al, 2003). These two proteins contain, respectively, seven and eight LRRs like those of the LHR-ECD: LxxLxLxxNxxLxxLPxxaFxxLxx (see Fig.…”

Section: The Lhr-ecd: Structure and Hormone Bindingmentioning

confidence: 99%

“…The sequence alignments derived from the two software programs were combined manually to produce the best templates for comparative modeling using the MODELLER (6v2) software program (Sali et al, 1995). The ECD of the Nogo receptor (He et al, 2003) and of glycoprotein Ibα (Huizinga et al, 2002) were used as templates for all five class B and C receptors. The orphan receptors (class B) contain almost twice the number of LRRs as the receptors in classes A and C, and therefore the template chosen to model this larger global structure of the class B receptors was the LRR-containing portion of the Listeria monocytogenes interalin A protein (Schubert et al, 2002).…”

Section: Modeling Of Other Representatives Members Of the Gphr Clustermentioning

confidence: 99%

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A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein

Puett

DeMars

et al. 2007

Molecular and Cellular Endocrinology

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The luteinizing hormone receptor (LHR) is one of eight members in a cluster of the rhodopsin family of the large G protein-coupled receptor (GPCR) superfamily that contains some 800-900 genes in the human genome. LHR, along with its paralogons, follicle stimulating hormone receptor (FSHR) and thyroid stimulating hormone receptor, form one of the three classes in this cluster; the two other classes contain the relaxin-binding GPCRs and orphan GPCRs. These GPCRs are characterized by a relatively large ectodomain (ECD) containing leucine-rich-repeats (LRRs); in the class of glycoprotein hormone receptors, the LRR region is capped by N-terminal and C-terminal cysteinerich regions. Binding of human chorionic gonadotropin (hCG) or luteinizing hormone to the LHR-ECD triggers a conformational change of the transmembrane region of the receptor facilitating binding and activation of Gs, followed by effector enzyme activation and subsequent intracellular signaling. Viewing LHR as a transmembrane anchoring protein that sequentially binds hCG and Gs to give the hCG-LHR-Gs complex, numerous interactions and conformational changes must be considered. There is, unfortunately, a paucity of structural data on LHR, but crystal structures exist for hCG, the homologous FSH-FSHR-ECD (N-terminal fragment) complex, rhodopsin (in the inactive state), an active form of Gαs (transducin), and the βγ heterodimer. Using a combined experimental (site-directed mutagenesis followed by characterization in transfected cells) and computational (homology modeling and molecular dynamics simulations) approach, good working models are being developed for the protein-protein interaction faces and, in some cases, the ensuing conformational changes induced by complex formation. hCG binding to the LHR-ECD appears to involve several LRRs; LHR activation can be described in terms of disrupting a network of H-bonds in the cytosolic halves of helices 1-3, 6, and 7; and binding of LHR to Gs involves, in large part, intracellular loop 2 binding, presumably to Gsα at its C-terminus. Major gaps exist in our understanding at the molecular level of the six-polypeptide chain complex, hCG-LHR-Gs, but considerable progress has been made in the past few years.

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Molecular Genetics of von Willebrand Disease

Bowen

2008

Encyclopedia of Life Sciences

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In 1926, Dr Erik von Willebrand first described the autosomal bleeding disorder that we now call von Willebrand disease (VWD). Since then, the protein responsible – eponomously named von Willebrand factor (VWF) – has been identified, the gene encoding the protein has been localized , the gene sequence has been determined and many mutations within the gene that lead to a deficiency or dysfunction of VWF and cause VWD have been characterized. Through the concerted efforts of scientists and clinicians, there is now considerable understanding of the molecular genetics of VWD and, through studies done both in vitro and in vivo , the mechanism of disease has been revealed for many of the characterized gene defects. Despite the complexities of both the VWF protein and its gene, we have a detailed picture of the molecular genetics of VWD. This review aims to provide an informative summary of current knowledge. Key concepts von Willebrand factor (VWF) is a polymeric (multimeric) blood protein that is essential for the initial stages of blood clot formation. VWF has several biological activities that are important for its role in haemostasis, including binding to platelet glycoprotein Ib, coagulation factor VIII, collagen. VWF has a complex biochemistry that is influenced by independent modifiers such as ABO blood group and the metalloprotease ADAMTS13. von Willebrand disease (VWD) is classified into three types according to the quantity and functional activity of VWF: type 1, type 2 and type 3. Type 2 VWD is further subdivided according the functional defect present: type 2A, 2B, 2M and 2N. The genetic basis for VWD is highly heterogeneous; the disease shows dominant inheritance for some mutations and recessive inheritance for others. Mutations that cause milder forms of the disease show variable penetrance and this, in part relates to other modifying factors such as ABO blood group and possibly ADAMTS13. The relationship between cause and effect is understood for some mutations but not for all.

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Structures of Glycoprotein Ibα and Its Complex with von Willebrand Factor A1 Domain

Cited by 527 publications

References 28 publications

Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome

Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome

A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein

Molecular Genetics of von Willebrand Disease

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