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Role of the Helix in Talin F3 Domain (F3 Helix) in Talin-Mediated Integrin Activation

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Abstract

Increases in ligand binding to cellular integrins (activation) play an important role in platelet and leukocyte function. Talin is necessary in vivo and sufficient in vitro for integrin αIIbβ3 activation. The precise mechanisms by which talin activates integrin are still being elucidated. In particular, talin undergoes conformational changes (around the F3 helix) and inserts the F3 helix into lipid bilayer; however, the connection between this lipid-inserting mechanism of talin and talin’s capacity to activate integrin has never been explored before. In this work, we used rational mutagenesis, modeled cell systems, and structural modeling to study the potential role of membrane-induced talin conformational changes in talin-mediated integrin activation. Mutations of the residues critical for talin F3 helix to insert into membrane completely abolished talin-mediated integrin activation without affecting the binding of talin to integrins. Furthermore, mutations of the lipid-binding sequences in talin F3 helix significantly reduced the capacity of talin to activate integrin. Our results suggest that the F3 helix may contribute to talin-mediated integrin activation.

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Abbreviations

DSC:

Differential scanning calorimetry

F3 helix:

The helix in talin F3 domain

FERM:

Four-point-one, ezrin, radixin, moesin domain

MFI:

Mean fluorescence intensity

pK401 or polyK401:

Poly-Lys from Lys401 to Lys404

TM:

Transmembrane domain

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Acknowledgements

The authors would like to thank Dr. Mark Ginsberg for his generous gifts of many research reagents. All of the authors contributed to the collection and analysis of the data and to the preparation of the report. The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This work is supported by the Sichuan Provincial Department of Science and Technology Supporting Project (No. 2015SZ0074 to Dr. Ang Li).

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    Authors and Affiliations

    1. Department of Pancreatic Surgery, West China Hospital, Sichuan University, 37 Guoxue Rd, Chengdu, Sichuan Province, China

      Ang Li, Ailin Wei, Yaliang Zhou & Weiming Hu

    2. Department of Vascular Surgery, West China Hospital, Sichuan University, 37 Guoxue Rd, Chengdu, Sichuan Province, China

      Qiang Guo

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    1. Ang Li
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    Correspondence to Weiming Hu.

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    Ang Li and Qiang Guo have contributed equally to this study.

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    Li, A., Guo, Q., Wei, A. et al. Role of the Helix in Talin F3 Domain (F3 Helix) in Talin-Mediated Integrin Activation. Cell Biochem Biophys 75, 79–86 (2017). https://doi.org/10.1007/s12013-017-0781-x

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    • DOI: https://doi.org/10.1007/s12013-017-0781-x

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