The Amino-terminal One-third of αIIb Defines the Ligand Recognition Specificity of Integrin αIIbβ3

Loftus, Joseph C.; Halloran, Carol; Ginsberg, Mark H.; Feigen, Larry P.; Zablocki, Jeffery A.; Smith, Jeffrey W.

doi:10.1074/jbc.271.4.2033

Cited by 79 publications

(62 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Employing ␣v/␣IIb chimeras, it has been reported that ligand recognition specificity of ␣ IIb ␤ 3 is regulated by the amino-terminal one third of the ␣ subunit that contains the amino-terminal 140 residues and first 2 divalent cation binding repeats of ␣IIb. 46 Because missense mutations in ␤ 3 affect the expression and function of ␤ 3 integrins differently, the key structure should lie in the ␣ subunits. Further investigation of the structures in the ␣ subunits that regulate the biosynthesis of the ␤ 3 integrins is underway.…”

Section: Discussionmentioning

confidence: 99%

Missense mutations in the β3 subunit have a different impact on the expression and function between αIIbβ3 and αvβ3

Tadokoro

Tomiyama

Honda

et al. 2002

Blood

View full text Add to dashboard Cite

belong to the ␤ 3 integrin subfamily. Although the ␤ 3 subunit is a key regulator for the biosynthesis of ␤ 3 integrins, it remains obscure whether missense mutations in ␤ 3 may induce the same defects in both ␣ IIb ␤ 3 and ␣ v ␤ 3 . In this study, it is revealed that thrombasthenic platelets with a His280Pro mutation in ␤ 3 , which is prevalent in Japanese patients with Glanzmann thrombasthenia, did contain significant amounts of ␣ v ␤ 3 (about 50% of control) using sensitive enzyme-linked immunosorbent assay. Expression studies showed that the His280Pro␤ 3 mutation impaired ␣ IIb ␤ 3 expression but not ␣ v ␤ 3 expression in 293 cells. To extend these findings, the effects of several ␤ 3 missense mutations leading to an impaired ␣ IIb ␤ 3 expression on ␣ v ␤ 3 function as well as expression was examined: Leu117Trp, Ser162Leu, Arg216Gln, Cys374Tyr, and a newly created Arg216Gln/Leu292Ser mutation. IntroductionIntegrins are a family of cell surface molecules that mediate cellular attachment to the extracellular matrix and cell cohesion and are involved in such diverse biologic processes as thrombus formation, angiogenesis, inflammation, and embryogenesis. 1 Integrins are ␣␤ heterodimers, and ␤ 3 is one of 8 known ␤ subunits. ␣ IIb ␤ 3 and ␣ v ␤ 3 belong to the ␤ 3 integrin subfamily and share the same ␤ subunit (␤ 3 ). 2,3 ␣ IIb ␤ 3 , whose expression is restricted to the megakaryocyte/platelet lineage, is a prototypic integrin that functions as a physiologic receptor for fibrinogen and von Willebrand factor and plays a crucial role in normal hemostasis and platelet aggregation. 4 On the other hand, ␣ v ␤ 3 is expressed in a number of tissues, such as platelets, endothelial cells, smooth muscle cells, and osteoclasts, and plays a key role in cell proliferation, cell migration, angiogenesis, and bone resorption. [5][6][7] Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by a quantitative or qualitative abnormality of ␣ IIb ␤ 3 and caused by a defect in either the ␣IIb or ␤ 3 gene. [8][9][10][11] The quantitative abnormality in GT can be divided into 2 groups: type I has a severe ␣ IIb ␤ 3 deficiency (Ͻ 5% of normal) with no or minimal clot retraction, and type II has a moderate ␣ IIb ␤ 3 deficiency (10%-20% of normal) with normal or only moderately diminished clot retraction. 8 The numbers of ␣ IIb ␤ 3 and ␣ v ␤ 3 expressed on the platelet surface are 40 000 to 80 000 molecules per platelet and about 100 molecules per platelet, respectively. 12 Previous studies have shown that ␣ IIb ␤ 3 and ␣ v ␤ 3 are synthesized by a similar mechanism. 13 The ␣IIb ␣v and ␤ 3 subunits are synthesized from separate messenger RNA transcripts, and the ␤ 3 subunit becomes associated with either pro␣IIb or pro␣v, single-chain precursor forms of ␣ subunits, in the endoplasmic reticulum. The pro␣ IIb ␤ 3 and pro␣ v ␤ 3 complex are then transported to the Golgi apparatus, where pro␣ subunits undergo sugar modification and endoproteolytic cleavage into heavy and light chains. After these process...

show abstract

Section: Discussionmentioning

confidence: 99%

Missense mutations in the β3 subunit have a different impact on the expression and function between αIIbβ3 and αvβ3

Tadokoro

Tomiyama

Honda

et al. 2002

Blood

View full text Add to dashboard Cite

show abstract

“…There is mounting evidence that the predicted loops between N-terminal repeats 2 and 3 (W3 4-1 loop) and within repeat 3 (W3 2-3 loop) are important for ligand binding in non-I-domain ␣subunits. 18,[40][41][42][43] Previous studies have shown that the N-terminal one-third of the ␣ subunit regulates ligand-recognition specificity of ␤ 3 integrins 44 and that residues 139-167 in ␣ v corresponding to the W3 4-1 loop are a cross-linking site for RGD peptides. 21 However, the ␣ v Y178 identified in this study is located in the predicted W3 2-3 loop, and none of the alanine substitutions within the W3 4-1 loop examined impaired ligand binding.…”

Section: Discussionmentioning

confidence: 99%

Ligand binding to integrin αvβ3requires tyrosine 178 in the αv subunit

Honda

Tomiyama

Pampori

et al. 2001

Blood

View full text Add to dashboard Cite

Integrin ␣ v ␤ 3 has been implicated in angiogenesis and other biological processes. However, the ligand-binding sites in ␣ v , a non-I-domain ␣ subunit, remain to be identified. Recently in ␣ IIb , the other partner of the ␤ 3 subunit, several discontinuous residues important for ligand binding were identified in the predicted loops between repeats 2 and 3 (W3 4-1 loop) and within repeat 3 (W3 2-3 loop). Based on these findings, alaninescanning mutagenesis in 293 cells was used to investigate the role of these loops (cys- teine IntroductionIntegrins are a large family of ␣␤ heterodimeric adhesion receptors that is often subdivided into groups based on 8 known integrin ␤ subunits. 1 The ␤ 3 -integrin subfamily is composed of ␣ v ␤ 3 , originally identified as the vitronectin receptor, and ␣ IIb ␤ 3 , a plateletspecific receptor for fibrinogen and von Willebrand factor. ␣ IIb ␤ 3 plays a crucial role in platelet aggregation, normal hemostasis, and pathological thrombus formation. 2 On the other hand, ␣ v ␤ 3 is expressed in a number of tissues, including platelets, endothelial cells, vascular smooth muscle cells, and osteoclasts, and it plays a key role in angiogenesis and bone resorption. 3,4 The ␣ IIb and ␣ v subunits are homologous and 36% identical in primary amino acid sequence, 5 and most ligands that bind to ␣ IIb ␤ 3 , including fibrinogen, von Willebrand factor, and vitronectin, also bind to ␣ v ␤ 3 . However, there are some distinctive features between these 2 integrins. 3 First, the ␣ IIb subunit has been found only in combination with ␤ 3 , whereas ␣ v can associate with at least 5 ␤ subunits (␤ 1 , ␤ 3 , ␤ 5 , ␤ 6 , and ␤ 8 ). 6 Second, some ligands, such as osteopontin, matrix metalloproteinase-2, and adenovirus penton base, bind to ␣ v ␤ 3 but not to ␣ IIb ␤ 3 . Third, treatment of ␣ IIb ␤ 3 with ethylenediamine tetraacetic acid (EDTA) at 37°C dissociates the complex into its individual subunits; ␣ v ␤ 3 remains a heterodimer. Finally, the ligand-binding function of ␣ v ␤ 3 , but not ␣ IIb ␤ 3 , is suppressed by calcium (Ca 2ϩ ). 7 Generally, all integrins require divalent cations for ligand recognition, and multiple residues important for ligand binding have been identified on both ␣ and ␤ subunits. 8 The N-terminal region of integrin ␣ subunits has 7 repeats of homologous sequences of about 60 amino acid residues. Some integrin ␣ subunits (eg, ␣ 2 , ␣ L , and ␣ M ) contain an inserted domain of about 200 amino acids residues (the I-domain) between the second and the third repeats in the ␣ subunit, which is critically involved in ligand binding. 9,10 The crystal structure of the I-domain has been determined, and the metal ion-dependent adhesion site (MIDAS) motif that contributes to cation binding, as well as ligand binding, has been clarified. 11 Interestingly, a MIDAS-like motif essential for the ligand-binding function was also identified in integrin ␤ subunits. 12,13 On the other hand, integrin ␣ subunits, such as ␣ v , ␣ IIb , and ␣ 4 , do not have the I-domain. The structural basis for the i...

show abstract

“…It is well established that the N-terminal regions of both the a and ~ subunits are involved in ligand binding [5][6][7][8][9], but the lack of structural information for either region means that interpretation of the role of specific residues involved in ligand binding is very difficult. The exception to this lack of information is the subset of integrin a subunits which contain von Willebrand factor A-type domains (known as VWFA domains, sometimes referred to as A-or I-domains).…”

Section: Introductionmentioning

confidence: 99%

A structure prediction for the ligand‐binding region of the integrin β subunit: evidence for the presence of a von Willebrand factor A domain

1997

View full text Add to dashboard Cite

The integrins are a family of cell surface receptors that mediate biologically important adhesive interactions. Integrin-Iigand binding has been extensively studied because of the potential for the development of anti-adhesive therapies, but the molecular basis of this interaction is still poorly understood. A conserved region near the N-terminus of the ~ subunit appears to be of particular importance in ligand binding, but to date this domain has not been expressed in isolation. As a prelude to expression and potential structure determination, we have performed a detailed structure prediction for this region. Primary, secondary and tertiary structure analyses indicate that the region folds into a von Willebrand factor A-domain, thereby potentially placing a previously characterised module at the centre of a key functional region.

show abstract

The Amino-terminal One-third of αIIb Defines the Ligand Recognition Specificity of Integrin αIIbβ3

Cited by 79 publications

References 56 publications

Missense mutations in the β3 subunit have a different impact on the expression and function between αIIbβ3 and αvβ3

Missense mutations in the β3 subunit have a different impact on the expression and function between αIIbβ3 and αvβ3

Ligand binding to integrin αvβ3requires tyrosine 178 in the αv subunit

A structure prediction for the ligand‐binding region of the integrin β subunit: evidence for the presence of a von Willebrand factor A domain

Contact Info

Product

Resources

About