Skip to main content

Advertisement

SpringerLink
Log in

On the activation and deactivation pathways of the Lck kinase domain: a computational study

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Here we report the description of the conformational pathways connecting the Lck active and inactive states by means of all-atoms molecular dynamics simulations coupled to an enhancing sampling methodology. By such an approach, we describe the major structural determinants characterizing these large conformational transitions and compare such pathways to those obtained for a similar kinase, i.e. c-Src. Our results show that both the activation and deactivation processes could follow distinct pathways, differentiated by the order by which the A-loop and the C-helix regions rearrange.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bromann PA, Korkaya H, Courtneidge SA (2004) The interplay between Src family kinases and receptor tyrosine kinases. Oncogene 23(48):7957–7968. https://doi.org/10.1038/sj.onc.1208079

    Article  CAS  PubMed  Google Scholar 

  2. Parsons SJ, Parsons JT (2004) Src family kinases, key regulators of signal transduction. Oncogene 23(48):7906–7909. https://doi.org/10.1038/sj.onc.1208160

    Article  CAS  PubMed  Google Scholar 

  3. Nika K, Soldani C, Salek M, Paster W, Gray A, Etzensperger R, Fugger L, Polzella P, Cerundolo V, Dushek O, Höfer T (2010) Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32(6):766–777. https://doi.org/10.1016/j.immuni.2010.05.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Palacios EH, Weiss A (2004) Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene 23(48):7990–8000. https://doi.org/10.1038/sj.onc.1208074

    Article  CAS  PubMed  Google Scholar 

  5. Goldman FD, Ballas ZK, Schutte BC, Kemp J, Hollenback C, Noraz N, Taylor N (1998) Defective expression of p56lck in an infant with severe combined immunodeficiency. J Clin Investig 102(2):421–429. https://doi.org/10.1172/JCI3205

    Article  CAS  PubMed  Google Scholar 

  6. Hubert P, Bergeron F, Ferreira R, Seligmann M, Oksenhendler E, Debre P, Autran B (2000) Defective p56 Lck activity in T cells from an adult patient with idiopathic CD4 lymphocytopenia. Int Immunol 12. https://pdfs.semanticscholar.org/3cc1/eb55b10ee553d570aec2d852e215d5a7e90e.pdf

  7. Lee JE, Cossoy MB, Chau LA, Singh B, Madrenas J (1997) Complexes of peptide:MHC molecules. Signaling upon persistent engagement with Inactivation of lck and loss of TCR-mediated. http://www.jimmunol.org/content/159/1/61

  8. Engen JR, Wales TE, Hochrein JM, Meyn MA, Banu Ozkan S, Bahar I, Smithgall TE (2008) Structure and dynamic regulation of Src-family kinases. Cell Mol Life Sci 65(19):3058–3073. https://doi.org/10.1007/s00018-008-8122-2

    Article  CAS  PubMed  Google Scholar 

  9. Boggon TJ, Eck MJ (2004) Structure and regulation of Src family kinases. Oncogene 23(48):7918–7927. https://doi.org/10.1038/sj.onc.1208081

    Article  CAS  PubMed  Google Scholar 

  10. Yamaguchi H, Hendrickson WA (1996) Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature 384(6608):484–489. https://doi.org/10.1038/384484a0

    Article  CAS  PubMed  Google Scholar 

  11. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298(5600):1912–1934. https://doi.org/10.1126/science.1075762

    Article  CAS  PubMed  Google Scholar 

  12. Kinnings SL, Jackson RM (2009) Binding site similarity analysis for the functional classification of the protein kinase family. J Chem Inf Model 49(2):318–329. https://doi.org/10.1021/ci800289y

    Article  CAS  PubMed  Google Scholar 

  13. Maier LM, Anderson DE, De Jager PL, Wicker LS, Hafler DA (2007) Allelic variant in CTLA4 alters T cell phosphorylation patterns. PNAS 104(47):18607–18612. https://doi.org/10.1073/pnas.0706409104

    Article  PubMed  Google Scholar 

  14. Ngoenkam J, Schamel WW, Pongcharoen S (2018) Selected signalling proteins recruited to the T-cell receptor-CD3 complex. Immunology 153(1):42–50. https://doi.org/10.1111/imm.12809

    Article  CAS  PubMed  Google Scholar 

  15. Abraham MJ, van der Spoel D, Lindahl E, Hess B, Team D (2017) GROMACS user manual version 2016.4. www.gromacs.org

  16. Huang W, Lin Z, van Gunsteren WF (2011) Validation of the GROMOS 54A7 force field with respect to β-peptide folding. J Chem Theory Comput 7(5):1237–1243. https://doi.org/10.1021/ct100747y

    Article  CAS  PubMed  Google Scholar 

  17. Mark P, Nilsson L (2001) Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. J Phys Chem A 105(43):9954–9960. https://doi.org/10.1021/jp003020w

    Article  CAS  Google Scholar 

  18. Swope WC, Andersen HC, Berens PH, Wilson KR (1982) A computer simulation method for the calculation of equilibrium constants for the formation of physical clusters of molecules: application to small water clusters. J Chem Phys 76(1):637–649. https://doi.org/10.1063/1.442716

    Article  CAS  Google Scholar 

  19. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N ·log(N) method for Ewald sums in large systems. J Chem Phys 98(12):10089–10092. https://doi.org/10.1063/1.464397

    Article  CAS  Google Scholar 

  20. Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126(1):014101. https://doi.org/10.1063/1.2408420

    Article  CAS  PubMed  Google Scholar 

  21. Amadei A, Linssen ABM, Berendsen HJC (1993) Essential dynamics of proteins. Proteins 17(4):412–425. https://doi.org/10.1002/prot.340170408

    Article  CAS  PubMed  Google Scholar 

  22. Hess B (2000) Similarities between principal components of protein dynamics and random diffusion. Phys Rev E 62(6):8438. https://doi.org/10.1103/PhysRevE.62.8438

    Article  CAS  Google Scholar 

  23. Bešker N, Amadei A, D’abramo M (2014) Molecular mechanisms of activation in CDK2. J Biomol Struct Dyn 32(12):1929–1935. https://doi.org/10.1080/07391102.2013.844080

    Article  CAS  PubMed  Google Scholar 

  24. Milanetti E, Trandafir AG, Alba J, Raimondo D, D’abramo M (2018) Efficient and accurate modeling of conformational transitions in proteins: the case of c-Src kinase. J Phys Chem 122(38):8853–8860. https://doi.org/10.1021/acs.jpcb.8b07155

    Article  CAS  Google Scholar 

  25. Johnson LN, Noble ME, Owen DJ (1996) Active and inactive protein kinases: structural basis for regulation. Cell 85(2):149–158. https://doi.org/10.1016/S0092-8674(00)81092-2

    Article  CAS  PubMed  Google Scholar 

  26. Meng Y, Shukla D, Pande VS, Roux B (2016) Transition path theory analysis of c-Src kinase activation. Proc Natl Acad Sci USA 113(33):9193–9198. https://doi.org/10.1073/pnas.1602790113

    Article  CAS  PubMed  Google Scholar 

  27. Yang S, Banavali NK, Roux B (2009) Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories. Proc Natl Acad Sci USA 106(10):3776–3781. https://doi.org/10.1073/pnas.0808261106

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partially funded by Sapienza, University of Rome (Progetto di Ateneo 2018). The authors gratefully acknowledge NVIDIA and CINECA for computational support.

Author information

Authors and Affiliations

  1. Department of Chemistry, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy

    Josephine Alba & Marco D’Abramo

  2. Center for Life Nano Science@Sapienza, Italian Institute of Technology, Viale Regina Elena 291, 00161, Rome, Italy

    Edoardo Milanetti

  3. Department of Physics, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy

    Edoardo Milanetti

Authors
  1. Josephine Alba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edoardo Milanetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco D’Abramo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco D’Abramo.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (MP4 7174 kb)

Supplementary material 2 (DOCX 6544 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alba, J., Milanetti, E. & D’Abramo, M. On the activation and deactivation pathways of the Lck kinase domain: a computational study. J Comput Aided Mol Des 33, 597–603 (2019). https://doi.org/10.1007/s10822-019-00204-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-019-00204-0

Keywords

Search

Navigation