Predicting the Specificity- Determining Positions of Receptor Tyrosine Kinase Axl

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Karakulak T., RİFAİOĞLU A. S., Rodrigues J. P. G. L. M., Karaca E.

FRONTIERS IN MOLECULAR BIOSCIENCES, cilt.8, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 8
  • Basım Tarihi: 2021
  • Doi Numarası: 10.3389/fmolb.2021.658906
  • Dergi Adı: FRONTIERS IN MOLECULAR BIOSCIENCES
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Directory of Open Access Journals
  • Anahtar Kelimeler: protein selectivity, sequence analysis, molecular dynamics, Axl, HADDOCK, DETECTING FUNCTIONAL SPECIFICITY, DETERMINING RESIDUES, EVOLUTIONARY CONSERVATION, SEQUENCE HARMONY, PROTEINS, CONSURF, REGIONS, GAS6
  • Dokuz Eylül Üniversitesi Adresli: Hayır

Özet

Owing to its clinical significance, modulation of functionally relevant amino acids in protein-protein complexes has attracted a great deal of attention. To this end, many approaches have been proposed to predict the partner-selecting amino acid positions in evolutionarily close complexes. These approaches can be grouped into sequence-based machine learning and structure-based energy-driven methods. In this work, we assessed these methods' ability to map the specificity-determining positions of Axl, a receptor tyrosine kinase involved in cancer progression and immune system diseases. For sequence-based predictions, we used SDPpred, Multi-RELIEF, and Sequence Harmony. For structure-based predictions, we utilized HADDOCK refinement and molecular dynamics simulations. As a result, we observed that (i) sequence-based methods overpredict partner-selecting residues of Axl and that (ii) combining Multi-RELIEF with HADDOCK-based predictions provides the key Axl residues, covered by the extensive molecular dynamics simulations. Expanding on these results, we propose that a sequence-structure-based approach is necessary to determine specificity-determining positions of Axl, which can guide the development of therapeutic molecules to combat Axl misregulation.