Glycoprotein Ib-IX-V complex
The GPIb-IX-V complex is a profuse
Molecular structure
Overview
GPIb-IX-V consists of four different subunits namely: GPIbα (
Each subunit of the complex is a type I
The quaternary stabilization of the receptor is facilitated by
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
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. This is with the exception of the gene for GPIbβ, which contains an intron 10 bases following the start codon.[3]
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.[8] Under normal conditions, all four molecules are expressed exclusively in the platelet lineage. GPIbα, GPIbβ and GPIX are necessary for the effective biosynthesis 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.[8][9]
GPIbα
Dissection of the crystal structure of the GPIbα N-terminal leucine rich repeat domain discloses the presence of a single disulfide bond between
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.[1][3]
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
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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.[1][6] Furthermore, GPV doesn’t appear to be critical for VWF binding or signal transduction.[7]
Role in disease
Abnormalities of the GPIb-V-IX complex result in abnormal appearance and functioning of platelets resulting in
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.[7]
References
- ^ PMID 23336709.
- ^ PMID 19726719.
- ^ PMID 9616133.
- ^ PMID 2436691.
- ^ PMID 17008541.
- ^ PMID 22759073.
- ^ PMID 21908432.
- ^ PMID 17109744.
- PMID 16102044.
- PMID 36740532.
- ^ Bernard J, Soulier JP (1948). "Sur une nouvelle variete de dystrophie thrombocythaire hemorragipare congenitale". Sem Hop Paris. 24: 3217–3223.
- PMID 16409472.