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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   +
1   Laboratoire Franco-Luxembourgeois de Recherche Biomédicale (CNRS/CRP-Santé), Centre Universitaire, Luxembourg
,
Chantal Melchior
1   Laboratoire Franco-Luxembourgeois de Recherche Biomédicale (CNRS/CRP-Santé), Centre Universitaire, Luxembourg
,
Ping Chen   ++
1   Laboratoire Franco-Luxembourgeois de Recherche Biomédicale (CNRS/CRP-Santé), Centre Universitaire, Luxembourg
,
Wim Ammerlaan
2   Département d’Immunologie, Laboratoire National de Santé, Luxembourg
,
Thomas Lecompte
3   Laboratoire d’Hematologie-UMR CNRS 7563, Faculté de Médecine, Vandoeuvre-les-Nancy, France
,
Cécile Kaplan
4   Institut National de la Transfusion Sanguine, Paris, France
,
Nelly Kieffer
1   Laboratoire Franco-Luxembourgeois de Recherche Biomédicale (CNRS/CRP-Santé), Centre Universitaire, Luxembourg
› Author Affiliations
Further Information

Publication History

Received 25 November 2000

Accepted after resubmission 19 September 2001

Publication Date:
12 December 2017 (online)

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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, p125FAK 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

* This work was supported by grants from Centre de Recherche Public-Santé (CRP-Santé, Luxembourg), and CNRS (France). +MC. M-K is a recipient of a European Community Marie Curie fellowship (ERBFMBICT 961531).


+ MC. M-K is a recipient of a European Community Marie Curie fellowship (ERBFMBICT 961531).


++ P.C is a recipient of a fellowship from the Ministère de la Coopération, Luxembourg.


 

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