Intramolecular Dynamics within the N-Cap-SH3-SH2 Regulatory Unit of the c-Abl Tyrosine Kinase Reveal Targeting to the Cellular Membrane |
| |
Authors: | Guilherme A. P. de Oliveira Elen G. Pereira Giulia D. S. Ferretti Ana Paula Valente Yraima Cordeiro Jerson L. Silva |
| |
Affiliation: | From the ‡Programa de Biologia Estrutural, Instituto de Bioquímica Médica, Instituto Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ and ;the §Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil |
| |
Abstract: | c-Abl is a key regulator of cell signaling and is under strict control via intramolecular interactions. In this study, we address changes in the intramolecular dynamics coupling within the c-Abl regulatory unit by presenting its N-terminal segment (N-Cap) with an alternative function in the cell as c-Abl becomes activated. Using small angle x-ray scattering, nuclear magnetic resonance, and confocal microscopy, we demonstrate that the N-Cap and the Src homology (SH) 3 domain acquire μs-ms motions upon N-Cap association with the SH2-L domain, revealing a stabilizing synergy between these segments. The N-Cap-myristoyl tether likely triggers the protein to anchor to the membrane because of these flip-flop dynamics, which occur in the μs-ms time range. This segment not only presents the myristate during c-Abl inhibition but may also trigger protein localization inside the cell in a functional and stability-dependent mechanism that is lost in Bcr-Abl+ cells, which underlie chronic myeloid leukemia. This loss of intramolecular dynamics and binding to the cellular membrane is a potential therapeutic target. |
| |
Keywords: | NMR Protein Dynamics Protein Structure Tyrosine Protein Kinase (Tyrosine Kinase) X-ray Scattering SAXS c-Abl Protein Chronic Myeloid Leukemia Myristoylation |
|
|