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Title

L718P mutation in the membrane-proximal cytoplasmic tail of [beta]3 promotes abnormal [alpha]IIb[beta]3 clustering and lipid microdomain coalescence, and associates to thrombasthenia-like phenotype

AuthorsJayo, Asier ; Conde, Isabel ; Lastres, Pedro ; Martínez, Constantino; Rivera, José; Vicente, Vicente; González-Manchón, Consuelo
KeywordsαIIbβ3 mutation
Integrin clustering
Lipid phase separation
Thrombasthenia
Issue Date2010
PublisherFerrata Storti Foundation
CitationHaematologica, 95 (7) : 1158-1166 (2010)
AbstractBackground Support for the role of transmembrane and membrane-proximal domains of αIIbβ3 integrin in the maintenance of receptor low affinity comes from mutational studies showing that activating mutations can induce constitutive bi-directional transmembrane signaling. Design and Methods We report the functional characterization of a mutant αIIbβ3 integrin carrying the Leu718Pro mutation in the membrane-proximal region of the β3 cytoplasmic domain, identified in heterozygosis in a patient with a severe bleeding phenotype and defective platelet aggregation and adhesion. Results Transiently transfected cells expressed similar levels of normal and mutant αIIbβ3, but surface expression of mutant αvβ3 was reduced due to its retention in intracellular compartments. Cells stably expressing mutant αIIbβ3 showed constitutive binding to soluble multivalent ligands as well as spontaneous fibrinogen-dependent aggregation, but their response to DTT was markedly reduced. Fibrinogen-adherent cells exhibited a peculiar spreading phenotype with long protrusions. Immunofluorescence analysis revealed the formation of αIIbβ3 clusters underneath the entire cell body and the presence of atypical high-density patches of clustered αIIbβ3 containing encircled areas devoid of integrin that showed decreased affinity for the fluorescent lipid analog DiIC16 and were disrupted in cholesterol-depleted cells. Conclusions These findings are consistent with an important role of the membrane-proximal region of β3 in modulating αIIbβ3 clustering and lateral redistribution of membrane lipids. Since the β3 mutant was associated with a thrombasthenic phenotype in a patient carrying one normal β3 allele, these results support a dominant role of clustering in regulating integrin αIIbβ3 functions in vivo
Description26 p.-6 fig.-5 fig. supp.
Publisher version (URL)http://dx.doi.org/10.3324/haematol.2009.018572
URIhttp://hdl.handle.net/10261/73523
DOI10.3324/haematol.2009.018572
ISSN0390-6078
E-ISSN1592-8721
Appears in Collections:(CIB) Artículos
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