The molecular basis of talin2's high affinity toward β1-integrin.
Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with Cys diminished that of talin2. Further computational modeling analysis shows that talin2 S339 formed a hydrogen bond with E353, which is critical for inducing key hydrogen bonds between talin2 N326 and β1-integrin R760, and between talin2 K327 and β1-integrin D759. Mutation at any of these residues significantly diminished the interaction of talin2 with β1- integrin tails. These hydrogen bonds were not observed in talin1/β1-integrin, but did exist in talin1C336S/β1-integrin complex. These results suggest that talin2 S339 forms a hydrogen bond with E353 to mediate its high affinity to β1-integrin.
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40506, USA.
Yaxia
Y
Yuan
Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.
Liqing
L
Li
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40506, USA.
Yanyan
Y
Zhu
Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.
Lei
L
Qi
BioMediTech, University of Tampere, 33520 Tampere, Finland and Fimlab Laboratories, 33520 Tampere, Finland.
Latifeh
L
Azizi
BioMediTech, University of Tampere, 33520 Tampere, Finland and Fimlab Laboratories, 33520 Tampere, Finland.
Vesa P
VP
Hytönen
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40506, USA.
Chang-Guo
CG
Zhan
Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Department of Pharmacology and nutritional sciences, University of Kentucky, Lexington, KY 40506, USA.
Cai
C
Huang
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D016608:Talin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D019012:Integrin beta1; D016608:Talin