Intramolecular dynamics within the N-Cap-SH3-SH2 regulatory unit of the c-Abl tyrosine kinase reveal targeting to the cellular membrane.
J Biol Chem
; 288(39): 28331-45, 2013 Sep 27.
Article
en En
| MEDLINE
| ID: mdl-23928308
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Leucemia Mielógena Crónica BCR-ABL Positiva
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Regulación Enzimológica de la Expresión Génica
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Regulación Leucémica de la Expresión Génica
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Membrana Celular
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Proteínas Proto-Oncogénicas c-abl
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2013
Tipo del documento:
Article
Pais de publicación:
Estados Unidos