Genetic analysis of beta1 integrin "activation motifs" in mice.
Akey feature of integrins is their ability to regulate the affinity for ligands, a process termed integrin activation. The final step in integrin activation is talin binding to the NPXY motif of the integrin beta cytoplasmic domains. Talin binding disrupts the salt bridge between the alpha/beta tails, leading to tail separation and integrin activation. We analyzed mice in which we mutated the tyrosines of the beta1 tail and the membrane-proximal aspartic acid required for the salt bridge. Tyrosine-to-alanine substitutions abolished beta1 integrin functions and led to a beta1 integrin-null phenotype in vivo. Surprisingly, neither the substitution of the tyrosines with phenylalanine nor the aspartic acid with alanine resulted in an obvious defect. These data suggest that the NPXY motifs of the beta1 integrin tail are essential for beta1 integrin function, whereas tyrosine phosphorylation and the membrane-proximal salt bridge between alpha and beta1 tails have no apparent function under physiological conditions in vivo.
Czuchra
Aleksandra
A
Max Planck Institute of Biochemistry, Department of Molecular Medicine, 82152 Martinsried, Germany.
Meyer
Hannelore
H
Legate
Kyle R
KR
Brakebusch
Cord
C
Fässler
Reinhard
R
D000409:Alanine / Q000737:chemistry / Q000235:genetics; D020816:Amino Acid Motifs / Q000235:genetics; D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry* / Q000235:genetics*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019012:Integrin beta1 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011940:Receptor Aggregation / Q000502:physiology; D012492:Salts / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics
D019012:Integrin beta1; D008024:Ligands; D021122:Protein Subunits; D012492:Salts; D014443:Tyrosine; D000409:Alanine