A Naturally Occurring Point Mutation in the β3 Integrin MIDAS-like Domain Affects Differently αvβ3 and αIIbβ3 Receptor Function

Marie-Christine Morel-Kopp; Chantal Melchior; Ping Chen; Wim Ammerlaan; Thomas Lecompte; Cécile Kaplan; Nelly Kieffer

doi:10.1055/s-0037-1616746

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 86(06): 1425-1434
DOI: 10.1055/s-0037-1616746

Review Article

Schattauer GmbH

A Naturally Occurring Point Mutation in the β3 Integrin MIDAS-like Domain Affects Differently αvβ3 and αIIbβ3 Receptor Function^[*]

Marie-Christine Morel-Kopp⁺

¹Laboratoire Franco-Luxembourgeois de Recherche Biomédicale (CNRS/CRP-Santé), Centre Universitaire, Luxembourg

,

Chantal Melchior

¹Laboratoire Franco-Luxembourgeois de Recherche Biomédicale (CNRS/CRP-Santé), Centre Universitaire, Luxembourg

,

Ping Chen⁺⁺

¹Laboratoire Franco-Luxembourgeois de Recherche Biomédicale (CNRS/CRP-Santé), Centre Universitaire, Luxembourg

,

Wim Ammerlaan

²Département d’Immunologie, Laboratoire National de Santé, Luxembourg

,

Thomas Lecompte

³Laboratoire d’Hematologie-UMR CNRS 7563, Faculté de Médecine, Vandoeuvre-les-Nancy, France

,

Cécile Kaplan

⁴Institut National de la Transfusion Sanguine, Paris, France

,

Nelly Kieffer

¹Laboratoire Franco-Luxembourgeois de Recherche Biomédicale (CNRS/CRP-Santé), Centre Universitaire, Luxembourg

› Author Affiliations

Abstract

Summary

We have investigated the effect of a new Leu¹⁹⁶Pro mutation, identified in the MIDAS-like domain of the β3 integrin subunit in a patient with type II Glanzmann thrombasthenia, on β3 integrin receptor function. Expression of the mutant β3Pro¹⁹⁶ subunit in CHO cells, either associated with recombinant human αIIb or αv, resulted in normal biosynthesis of β3 and heterodimerization with αv or IIb, but selectively interfered with αIIbβ3 maturation and transport to the cell surface. Functional analysis of the β3 mutant receptors revealed strong inhibition of αvβ3-mediated cell spreading on immobilized fibrinogen, focal contact formation, p125^FAK phosphorylation and fibrin clot retraction, as opposed to normal αIIbβ3-mediated cell interaction with immobilized fibrinogen, focal contact translocation and signaling. In contrast, antibody- or DTT-activated mutant αIIbβ3 was unable to bind soluble fibrinogen or the ligand mimetic PAC-1 monoclonal antibody, but underwent a conformational change following RGD peptide binding as demonstrated by AP5-LIBS epitope expression. These results suggest that (1) the highly conserved TL¹⁹⁶T motif in the β3 integrin subunit is located in a domain structurally important for the exposure of a functional binding site for soluble fibrinogen; and (2) that the MIDAS-like contact site in β3 is not involved in αIIbβ3-mediated cell adhesion to immobilized fibrinogen, while it is essential for αvβ3-mediated interaction with this ligand.

Keywords

Glanzmann thrombasthenia - 3 integrins - fibrinogen receptor - cell adhesion

Full Text

References

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A Naturally Occurring Point Mutation in the β3 Integrin MIDAS-like Domain Affects Differently αvβ3 and αIIbβ3 Receptor Function[*]

A Naturally Occurring Point Mutation in the β3 Integrin MIDAS-like Domain Affects Differently αvβ3 and αIIbβ3 Receptor Function^[*]