MODELING CELL PROLIFERATION ACTIVITY OF HUMAN INTERLEUKIN-3 UPON SINGLE RESIDUE REPLACEMENTS

Majid Masso, Iosif I. Vaisman

Abstract

The signaling molecule human interleukin-3 (IL-3) is responsible for promoting the growth of a wide range of hematopoietic cell lineages in the bone marrow. In this study, we apply an in silico mutagenesis technique to investigate the effects of single amino acid substitutions in the IL-3 protein on cell proliferation activity. The computational mutagenesis, which utilizes the IL-3 protein structure as well as a knowledge-based, four-body statistical potential, empirically quantifies environmental perturbations at the mutated residue position in IL-3 and at all neighboring positions in the folded structure. In particular, mutated position perturbation scores alone are capable of characterizing IL-3 residues grouped by physicochemical, functional, or structural properties. Additionally, these scores elucidate an IL-3 structure–function relationship based on a collection of 630 single residue replacements for which activity changes were experimentally measured. A random forest classifier trained on this dataset of experimental mutants, whose respective feature vectors include environmental changes at the mutated position and at six nearest neighbors in the IL-3 structure, achieves 80% accuracy and outperforms related state-of-the-art methods.

References

  1. Bagley, C. J., Phillips, J., Cambareri, B., Vadas, M. A. and Lopez, A. F. (1996) J Biol Chem, 271, 31922-31928.
  2. Baldi, P., Brunak, S., Chauvin, Y., Andersen, C. A. and Nielsen, H. (2000) Bioinformatics, 16, 412-424.
  3. Barber, C. B., Dobkin, D. P. and Huhdanpaa, H. T. (1996) ACM Trans Math Software, 22, 469-483.
  4. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N. and Bourne, P. E. (2000) Nucleic Acids Res, 28, 235-242.
  5. Bordner, A. J. (2008) Bioinformatics, 24, 2865-2871.
  6. Bowie, J. U., Luthy, R. and Eisenberg, D. (1991) Science, 253, 164-170.
  7. Breiman, L. (2001) Machine Learning, 45, 5-32.
  8. Bromberg, Y. and Rost, B. (2007) Nucleic Acids Res, 35, 3823-3835.
  9. Capriotti, E., Calabrese, R. and Casadio, R. (2006) Bioinformatics, 22, 2729-2734.
  10. Carter, C. W., Jr., LeFebvre, B. C., Cammer, S. A., Tropsha, A. and Edgell, M. H. (2001) J Mol Biol, 311, 625-38.
  11. Dayhoff, M. O., Schwartz, R. M. and Orcut, B. C. (1978) In Atlas of Protein Sequence and Structure, Vol. 5 (Ed, Dayhoff, M. O.) National Biomedical Research Foundation, Washington D.C., pp. 345-352.
  12. de Berg, M., Cheong, O., van Kreveld, M. and Overmars, M. (2008) Computational Geometry: Algorithms and Applications, Springer-Verlag, Berlin.
  13. Fawcett, T. (2003) In Technical Report HPL-2003-4. Hewlett-Packard Labs, Palo Alto.
  14. Feng, Y., Klein, B. K. and McWherter, C. A. (1996) J Mol Biol, 259, 524-541.
  15. Frank, E., Hall, M., Trigg, L., Holmes, G. and Witten, I. H. (2004) Bioinformatics, 20, 2479-2481.
  16. Klein, B. K., Feng, Y., McWherter, C. A., Hood, W. F., Paik, K. and McKearn, J. P. (1997) J Biol Chem, 272, 22630-22641.
  17. Kyte, J. and Doolittle, R. F. (1982) J Mol Biol, 157, 105- 132.
  18. Ng, P. C. and Henikoff, S. (2006) Annu Rev Genomics Hum Genet, 7, 61-80.
  19. Olins, P. O., Bauer, S. C., Braford-Goldberg, S., Sterbenz, K., Polazzi, J. O., Caparon, M. H., Klein, B. K., Easton, A. M., Paik, K., Klover, J. A. and et al. (1995) J Biol Chem, 270, 23754-23760.
  20. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C. and Ferrin, T. E. (2004) J Comput Chem, 25, 1605-1612.
  21. Qi, Y., Bar-Joseph, Z. and Klein-Seetharaman, J. (2006) Proteins, 63, 490-500.
  22. Sippl, M. J. (1993) J Comput Aided Mol Des, 7, 473-501.
  23. Wang, G. and Dunbrack, R. L., Jr. (2003) Bioinformatics, 19, 1589-1591.
  24. Zhang, S., Kaplan, A. H. and Tropsha, A. (2008) Proteins, 73, 742-53.
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Paper Citation


in Harvard Style

Masso M. and I. Vaisman I. (2011). MODELING CELL PROLIFERATION ACTIVITY OF HUMAN INTERLEUKIN-3 UPON SINGLE RESIDUE REPLACEMENTS . In Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011) ISBN 978-989-8425-36-2, pages 93-101. DOI: 10.5220/0003112700930101


in Bibtex Style

@conference{bioinformatics11,
author={Majid Masso and Iosif I. Vaisman},
title={MODELING CELL PROLIFERATION ACTIVITY OF HUMAN INTERLEUKIN-3 UPON SINGLE RESIDUE REPLACEMENTS},
booktitle={Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011)},
year={2011},
pages={93-101},
publisher={SciTePress},
organization={INSTICC},
doi={10.5220/0003112700930101},
isbn={978-989-8425-36-2},
}


in EndNote Style

TY - CONF
JO - Proceedings of the International Conference on Bioinformatics Models, Methods and Algorithms - Volume 1: BIOINFORMATICS, (BIOSTEC 2011)
TI - MODELING CELL PROLIFERATION ACTIVITY OF HUMAN INTERLEUKIN-3 UPON SINGLE RESIDUE REPLACEMENTS
SN - 978-989-8425-36-2
AU - Masso M.
AU - I. Vaisman I.
PY - 2011
SP - 93
EP - 101
DO - 10.5220/0003112700930101