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A molecular arm: the molecular bending–unbending mechanism of integrin

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Abstract

The balance of integrin activation and deactivation regulates its function and mediates cell behaviors. Mechanical force triggers the unbending and activation of integrin. However, how an activated and extended integrin spontaneously bends back is unclear. I performed all-atom molecular dynamics simulations on an integrin or its subunits to reveal the bending-unbending mechanism of integrin. According to the simulations, the integrin structure works like a human arm. The integrin α subunit serves as the bones, while the β leg serves as the bicep. The integrin extension results in the stretching of the β leg, and the extended integrin spontaneously bends as a consequence of the contraction of the β leg. This study provides new insights into the mechanism of how the integrin secures in the bent inactivated state and sheds light on how the integrin could achieve a stable extended state.

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References

  • Bennett JS, Berger B, Billings P (2009) The structure and function of platelet integrins. J Thromb Haemost 7:200–205

    Article  CAS  PubMed  Google Scholar 

  • Berendsen HJ, van der Spoel D, van Drunen R (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56

    Article  ADS  CAS  Google Scholar 

  • Bidone TC et al (2019) Coarse-grained simulation of full-length integrin activation. Biophys J 116:1000–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bouvard D et al (2003) Disruption of focal adhesions by integrin cytoplasmic domain-associated protein-1α. J Biol Chem 278:6567–6574

    Article  CAS  PubMed  Google Scholar 

  • Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101

    Article  ADS  PubMed  Google Scholar 

  • Calderwood DA et al (2003) Integrin β cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc Natl Acad Sci 100:2272–2277

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen W, Lou J, Hsin J, Schulten K, Harvey SC, Zhu C (2011) Molecular dynamics simulations of forced unbending of integrin αVβ3. PLoS Comput Biol 7:e1001086

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen W, Lou J, Evans EA, Zhu C (2012) Observing force-regulated conformational changes and ligand dissociation from a single integrin on cells. J Cell Biol 199:497–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Kong F, Li Z, Ju LA, Zhu C (2024) Force-Regulated Spontaneous Conformational Changes of Integrins α5β1 and αVβ3. ACS Nano 18:299–313

  • Driscoll TP, Bidone TC, Ahn SJ, Yu A, Groisman A, Voth GA, Schwartz MA (2021) Integrin-based mechanosensing through conformational deformation. Biophys J 120:4349–4359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elosegui-Artola A et al (2014) Rigidity sensing and adaptation through regulation of integrin types. Nat Mater 13:631–637

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferrenberg AM, Swendsen RH (1989) Optimized monte carlo data analysis. Comput Phys 3:101–104

    Article  ADS  Google Scholar 

  • Foloppe N, MacKerell J, Alexander D (2000) All-atom empirical force field for nucleic acids: I. Parameter optimization based on small molecule and condensed phase macromolecular target data. J Comput Chem 21:86–104

    Article  CAS  Google Scholar 

  • Haydari Z, Shams H, Jahed Z, Mofrad MR (2020) Kindlin assists talin to promote integrin activation. Biophys J 118:1977–1991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hub JS, De Groot BL, van der Spoel D (2010) g_wham—A free weighted histogram analysis implementation including robust error and autocorrelation estimates. J Chem Theory Comput 6:3713–3720

    Article  CAS  Google Scholar 

  • Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687

    Article  CAS  PubMed  Google Scholar 

  • Kamata T, Ambo H, Puzon-McLaughlin W, Tieu KK, Handa M, Ikeda Y, Takada Y (2004) Critical cysteine residues for regulation of integrin alphaIIbbeta3 are clustered in the epidermal growth factor domains of the beta3 subunit. Biochem J 378:1079–1082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katsumi A, Orr AW, Tzima E, Schwartz MA (2004) Integrins in mechanotransduction. J Biol Chem 279:12001–12004

    Article  CAS  PubMed  Google Scholar 

  • Kiema T et al (2006) The molecular basis of filamin binding to integrins and competition with talin. Mol Cell 21:337–347

    Article  CAS  PubMed  Google Scholar 

  • Kim M, Carman CV, Springer TA (2003) Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301:1720–1725

    Article  ADS  CAS  PubMed  Google Scholar 

  • Levin L, Zelzion E, Nachliel E, Gutman M, Tsfadia Y, Einav Y (2013) A single disulfide bond disruption in the β3 integrin subunit promotes thiol/disulfide exchange, a molecular dynamics study. PLoS ONE 8:e59175

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Springer TA (2017) Integrin extension enables ultrasensitive regulation by cytoskeletal force. Proc Natl Acad Sci 114:4685–4690

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, Lee H, Zhu C (2016) Molecular mechanisms of mechanotransduction in integrin-mediated cell-matrix adhesion. Exp Cell Res 349:85–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J et al (2017) Conformational equilibria and intrinsic affinities define integrin activation. EMBO J 36:629–645

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo B-H, Strokovich K, Walz T, Springer TA, Takagi J (2004) Allosteric β1 integrin antibodies that stabilize the low affinity state by preventing the swing-out of the hybrid domain. J Biol Chem 279:27466–27471

    Article  CAS  PubMed  Google Scholar 

  • Luo B-H, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacKerell AD Jr et al (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586–3616

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto A, Kamata T, Takagi J, Iwasaki K, Yura K (2008) Key interactions in integrin ectodomain responsible for global conformational change detected by elastic network normal-mode analysis. Biophys J 95:2895–2908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mehrbod M, Trisno S, Mofrad MR (2013) On the activation of integrin αIIbβ3: outside-in and inside-out pathways. Biophys J 105:1304–1315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer EE, Rosenberg KJ, Israelachvili J (2006) Recent progress in understanding hydrophobic interactions. Proc Natl Acad Sci 103:15739–15746

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Mor-Cohen R (2016) Disulfide bonds as regulators of integrin function in thrombosis and hemostasis. Antioxid Redox Signal 24:16–31

    Article  CAS  PubMed  Google Scholar 

  • Mor-Cohen R et al (2012) Unique disulfide bonds in epidermal growth factor (EGF) domains of β3 affect structure and function of αIIbβ3 and αvβ3 integrins in different manner. J Biol Chem 287:8879–8891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagae M, Re S, Mihara E, Nogi T, Sugita Y, Takagi J (2012) Crystal structure of α5β1 integrin ectodomain: atomic details of the fibronectin receptor. J Cell Biol 197:131–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishimura T, Kaibuchi K (2007) Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev Cell 13:15–28

    Article  CAS  PubMed  Google Scholar 

  • Nosé S, Klein M (1983) Constant pressure molecular dynamics for molecular systems. Mol Phys 50:1055–1076

    Article  ADS  Google Scholar 

  • Parrinello M, Rahman A (1981) Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 52:7182–7190

    Article  ADS  CAS  Google Scholar 

  • Passam F et al (2018) Mechano-redox control of integrin de-adhesion. Elife 7:e34843

    Article  PubMed  PubMed Central  Google Scholar 

  • Paul S, Venkatramani R (2021) Estimating the directional flexibility of proteins from equilibrium thermal fluctuations. J Chem Theory Comput 17:3103–3118

    Article  CAS  PubMed  Google Scholar 

  • Pouwels J, Nevo J, Pellinen T, Ylänne J, Ivaska J (2012) Negative regulators of integrin activity. J Cell Sci 125:3271–3280

    CAS  PubMed  Google Scholar 

  • Puklin-Faucher E, Sheetz MP (2009) The mechanical integrin cycle. J Cell Sci 122:179–186

    Article  CAS  PubMed  Google Scholar 

  • Puklin-Faucher E, Vogel V (2009) Integrin activation dynamics between the RGD-binding site and the headpiece hinge. J Biol Chem 284:36557–36568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puklin-Faucher E, Gao M, Schulten K, Vogel V (2006) How the headpiece hinge angle is opened: new insights into the dynamics of integrin activation. J Cell Biol 175:349–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ross TD, Coon BG, Yun S, Baeyens N, Tanaka K, Ouyang M, Schwartz MA (2013) Integrins in mechanotransduction. Curr Opin Cell Biol 25:613–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shams H, Mofrad MR (2017) α-Actinin induces a kink in the transmembrane domain of β3-integrin and impairs activation via talin. Biophys J 113:948–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheu S-Y, Yang D-Y, Selzle H, Schlag E (2003) Energetics of hydrogen bonds in peptides. Proc Natl Acad Sci 100:12683–12687

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Smagghe BJ, Huang P-S, Ban Y-EA, Baker D, Springer TA (2010) Modulation of integrin activation by an entropic spring in the β-knee. J Biol Chem 285:32954–32966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su S, Ling Y, Fang Y, Wu J (2022) Force-enhanced biophysical connectivity of platelet β3 integrin signaling through Talin is predicted by steered molecular dynamics simulations. Sci Rep 12:1–11

    CAS  Google Scholar 

  • Tajik A et al (2016) Transcription upregulation via force-induced direct stretching of chromatin. Nat Mater 15:1287–1296

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Takagi J, Petre BM, Walz T, Springer TA (2002) Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110:599–611

    Article  CAS  PubMed  Google Scholar 

  • Torrie GM, Valleau JP (1977) Nonphysical sampling distributions in Monte Carlo free-energy estimation: umbrella sampling. J Comput Phys 23:187–199

    Article  ADS  Google Scholar 

  • Varga-Szabo D, Pleines I, Nieswandt B (2008) Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol 28:403–412

    Article  CAS  PubMed  Google Scholar 

  • Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH, Campbell ID (2007) Structural basis of integrin activation by talin. Cell 128:171–182

    Article  CAS  PubMed  Google Scholar 

  • Xiao T, Takagi J, Coller BS, Wang J-H, Springer TA (2004) Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432:59–67

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong J-P et al (2001) Crystal structure of the extracellular segment of integrin αVβ3. Science 294:339–345

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong J-P et al (2009) Crystal structure of the complete integrin αVβ3 ectodomain plus an α/β transmembrane fragment. J Cell Biol 186:589–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Wang H (2012) Integrin signalling and function in immune cells. Immunology 135:268–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou D, Thinn AMM, Zhao Y, Wang Z, Zhu J (2018) Structure of an extended β3 integrin Blood. J Am Soc Hematol 132:962–972

    CAS  Google Scholar 

  • Zhu J, Zhu J, Springer TA (2013) Complete integrin headpiece opening in eight steps. J Cell Biol 201:1053–1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work is supported by grants from the National Natural Science Foundation of China (12272216 and 12172204) and the Natural Science Foundation of Shanghai (22ZR1423500). A special thanks to Monique Xu for providing the elegant drawing of the human arm.

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Authors and Affiliations

  1. Shanghai Institute of Applied Mathematics and Mechanics, Shanghai Key Laboratory of Mechanics in Energy Engineering, Shanghai Frontier Science Center of Mechanoinformatics, School of Mechanics and Engineering Science, Shanghai University, Shanghai, 200072, China

    Zhenhai Li

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  1. Zhenhai Li
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ZL designed the study. ZL performed the MD simulation. ZL analyzed data. ZL wrote the manuscript.

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Correspondence to Zhenhai Li.

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Li, Z. A molecular arm: the molecular bending–unbending mechanism of integrin. Biomech Model Mechanobiol (2024). https://doi.org/10.1007/s10237-023-01805-3

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