The GPIb-IX-V complex is a profuse

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

complex originating in

megakaryocytes A megakaryocyte () is a large bone marrow cell with a lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal clotting. In humans, megakaryocytes usually account for 1 out of 10,000 bone marrow cells, but ca ...

and exclusively functional on the surface of

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

. It primarily functions to mediate the first critical step in platelet adhesion, by facilitating binding to

von Willebrand factor Von Willebrand factor (VWF) () is a blood glycoprotein that promotes primary hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thro ...

(VWF) on damaged sub-endothelium under conditions of high fluid

shear stress Shear stress (often denoted by , Greek alphabet, Greek: tau) is the component of stress (physics), stress coplanar with a material cross section. It arises from the shear force, the component of force vector parallel to the material cross secti ...

. Although the primary

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

for the GPIb-V-IX receptor is VWF, it can also bind to a number of other

ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...

in the circulation such as

thrombin Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...

P-selectin P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene. P-selectin functions as a cell adhesion molecule (CAM) on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and a ...

factor XI Factor XI, or plasma thromboplastin antecedent, is the zymogen form of factor XIa, one of the enzymes involved in coagulation. Like many other coagulation factors, it is a serine protease. In humans, factor XI is encoded by ''F11'' gene. Fu ...

factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein involved in coagulation. It is the zymogen form of factor XIIa (), an enzyme of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by ' ...

, high molecular weight

kininogen Kininogens are Protein precursor, precursor proteins for Kinin, kinins, biologically active Peptide, polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, Inflammation, inflammatory regulation, and the regulation of t ...

as well as

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

. GPIb-IX-V offers a critical role in

thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

, and the life cycle of platelets, and is implicated in a number of thrombotic pathological processes such as

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

Molecular structure

Overview

GPIb-IX-V consists of four different subunits namely: GPIbα ( molecular weight (MW) 135

kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...

), GPIbβ (MW 26 kDa), GPIX (MW 20 kDa) and GPV (MW 82kDa). The complex is assembled such that GPIbα, GPIbβ and GPIX form a highly integrated

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

complex in a 1:2:1 stoichiometry; and this associates weakly with GPV resulting in an overall stoichiometric ratio of 1:1. Each subunit of the complex is a type I

transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...

(TM) protein which consists of a

leucine-rich repeat A leucine-rich repeat (LRR) is a protein structural motif that forms an α/β horseshoe tertiary structure, fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine. These Pr ...

(LRR)

ectodomain An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A n ...

(extracellular domain), a single transmembrane helix, and a relatively short

cytoplasmic The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...

tail that lacks

enzymatic An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as produc ...

activity. The quaternary stabilization of the receptor is facilitated by

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

and

non-covalent In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The ...

interactions. The GPIbα subunit is linked to two GPIbβ subunits via membrane-proximal

disulfide bonds In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In in ...

, while GPIX associates itself tightly through non-covalent interactions with GPIb. The concomitant expression of all three subunits is required to allow the effective expression of GPIb-IX on the

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

cell surface and analysis of receptor expression in transfected Chinese hamster ovary (CHO) cells has further supported that the interaction between these subunits also acts to stabilize them. Each of the four subunits (GPIbα, GPIbβ, GPIX and GPV) is part of the leucine rich repeat motif superfamily. These leucine rich repeat sequences tend to be about 24

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

in length either occurring singly or in

tandem repeats In genetics, tandem repeats occur in DNA when a pattern of one or more nucleotides is repeated and the repetitions are directly adjacent to each other, e.g. ATTCG ATTCG ATTCG, in which the sequence ATTCG is repeated three times. Several protein ...

flanked by conserved

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

and

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

disulfide loop structures. Nevertheless, even though these structural similarities exist, distinctive

genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

that exist on different

chromosomes A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most importa ...

of the

genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...

code for the

polypeptides Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ami ...

that make up the GPIb-V-IX complex. The four genes that code for the components of the receptor in humans have a simple organization in which the coding sequence is contained within a single

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

. This is with the exception of the gene for GPIbβ, which contains an

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...

10 bases following the

start codon The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and archaea and a ''N''-formylmethionine (fMet) in bacteria, mitochondria and plastids. ...

. Human GPIbα is the product of a gene on chromosome 17 specifically 17p12, GPIbβ is the product of a gene on chromosome 22 specifically 22q11.2, while GPV and GPIX are products of genes found on chromosome 3 specifically 3q21 and 3q29 respectively. Under normal conditions, all four molecules are expressed exclusively in the platelet lineage. GPIbα, GPIbβ and GPIX are necessary for the effective

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

of the receptor and are closely associated at the platelet membrane. Typically, a lack of a single subunit significantly decreases the surface expression of the entire receptor complex.

GPIbα

GPIbα (CD42b) consisting of 610 amino acids is the major subunit and contains all known

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

ligand-binding sites of the complex for example: the A1 domain of von Willebrand factor (VWF) has a binding region as marked in the N-terminal domain of GPIbα; while the

binding site is contained in a conformationally flexible acidic residue-rich sequence containing sulfated tyrosines. Dissection of the crystal structure of the GPIbα N-terminal leucine rich repeat domain discloses the presence of a single disulfide bond between

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

(Cys) residues Cys4 and Cys17 in the N-capping region, and two disulfide bonds (Cys209-Cys248 and Cys211-Cys264) in the C-capping region. Furthermore, there are seven tandem leucine rich repeats and their flanking sequences in the central parallel β-coil region. This parallel β-coil region is made up of three sided coils stacked in layers and contains two

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

residues (Asn21 and Asn159), which serve as

N-glycosylation ''N''-linked glycosylation is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), i ...

sites. Following the leucine rich repeat domain is the acidic residue-rich sequence containing sulfated tyrosines, the highly O-glycosylated macroglycopeptide, a stalk region of about 40 to 50 residues, a single transmembrane sequence and finally a cytoplasmic tail containing 96 amino acid residues which includes

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

residues such as Ser587, Ser590 and Ser609 that can be

phosphorylated In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

GPIbβ, GPIX, GPV

GPIbβ (CD42c) contains 181 amino acids. In the extracellular domain (ectodomain), both the N-capping and C-capping regions, which flank the leucine rich repeat sequence, contain two interlocking disulfide bonds. Furthermore, there is only a single leucine-rich repeat giving rise to a much less curved parallel β-coil region as compared to that in GPIbα. GPIbβ contains only one N-glycosylation site (Asn41) and is disulfide linked to GPIbα immediately proximal to the plasma membrane of the platelet via Cys122 located at the junction of the extracellular and transmembrane domains. The GPIbβ cytoplasmic domain has a sequence of 34 amino acids. The region adjacent to the membrane is enriched in basic residues and Ser166 found more distally is phosphorylated and appears to have a role in platelet

cytoskeletal The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all Cell (biology), cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane ...

rearrangement.

GPIX Glycoprotein IX (platelet) (GP9) also known as CD42a (Cluster of Differentiation 42a), is a human gene. Platelet glycoprotein IX (GP9) is a small membrane glycoprotein found on the surface of human platelets. It forms a 1-to-1 noncovalent comple ...

(CD42a) contains 160 amino acids. The extracellular domain, which also only has a single leucine rich repeat sequence shares more than 45% sequence identity with GPIbβ counterpart. However, the transmembrane and cytoplasmic sequences are considerably different. The GPIX cytoplasmic tail is short consisting of 8 residues and is not known to associate with

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

proteins. There is also a

residue (Cys154) located at the junction of the transmembrane and cytoplasmic domains. The extracellular domain of GPV contains 13 leucine rich repeats flanked by N- and C- capping regions both containing two interlocking disulfide bonds. This is followed by a stalk region, the transmembrane sequence and a short cytoplasmic tail rich in basic residues. The GPV (CD42d) subunit is only weakly associated with the GPIb-IX part of the receptor complex through interactions between the transmembrane domains and has little impact on the surface expression of GPIb-IX, although GPIb-IX is required for efficient expression of GPV. Furthermore, GPV doesn’t appear to be critical for VWF binding or

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...

Role in disease

Abnormalities of the GPIb-V-IX complex result in abnormal appearance and functioning of platelets resulting in

Bernard–Soulier syndrome Bernard–Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder that is caused by a deficiency of the '' glycoprotein Ib-IX-V complex'' (GPIb-IX-V), the receptor for von Willebrand factor. The incidence of BSS is estimated to be ...

(BSS), a condition first described by Bernard J and Soulier J.P. It is a rare hereditary bleeding disorder most commonly with an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

inheritance and diagnosed based on prolonged skin-bleeding time, a reduced number of very large platelets (macrothrombocytopenia) and defective

ristocetin Ristocetin is a glycopeptide antibiotic, obtained from ''Amycolatopsis lurida'', previously used to treat staphylococcal infections. It is no longer used clinically because it caused thrombocytopenia and platelet agglutination. It is now used so ...

-induced platelet agglutination. Bernard Soulier Syndrome is characterized by little or no expression of GPIb-IX on the surface of platelets which in turn has the same effect on GPV. There have been a number of mutations associated with BSS patients that have been mapped to GPIbα, GPIbβ and GPIX demonstrating that all three subunits are required for effective surface expression of the complex on platelets.

References

{{Reflist Glycoproteins Transmembrane receptors