Non-receptor tyrosine kinases of the Src family play a major role in cellular transduction pathways such as cell growth, differentiation, transcription, proliferation, adhesion and survival. The proteins of the Src family encompass of six functional domains: Src homology domain 4 (SH4), Unique domain, SH3, SH2, a catalytic domain SH1 and C-terminal regulatory end. The SH4 domain consists of 15 to17 amino acid residues (res) that help binding non-receptor protein tyrosine kinase (PTK) to the cell membrane and regulating the depalmitylation and repalmitylation processes, mechanisms for changing localization in response to the cellular stimulation. The amino acid residues from 18-85 correspond to the unique domain, which is responsible for the interaction of PTK with specific receptor and protein targets. The N-terminal region (SH4-U domain, res1-85) is intrinsically disordered (ID) and thus limited structural data is available. In addition, there is a lack of understanding of how its interactions with other domains affect protein function. We performed a small angle X-ray scattering experiment to study the ensemble-averaged structure of the regulatory region of c-Src kinase, which includes SH4-U, SH3 and SH2 domains (res1-250). Furthermore, Hamiltonian replica-exchange molecular dynamic simulation, a method that enhances conformational sampling was implemented to investigate the large number of conformational sub-states visited in the complex protein free energy landscape. The results from simulation and experiment are in good agreement, signifying ID domain is flexible with a fully extended structure when isolated, whereas it attains less extended structure, but preserving the flexibility upon bound to SH3 and SH2 domains. The recent update from the simulation and experiment will be presented.

Intramolecular interaction in N-terminal regulatory region of c-Src kinase: A combined study of molecular dynamic simulation and small-angle scattering

255th National Meeting (2018)

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