Communication routes in ARID domains between distal residues in helix 5 and the DNA-binding loops.
PLoS Comput Biol
; 10(9): e1003744, 2014 Sep.
Article
em En
| MEDLINE
| ID: mdl-25187961
ABSTRACT
ARID is a DNA-binding domain involved in several transcriptional regulatory processes, including cell-cycle regulation and embryonic development. ARID domains are also targets of the Human Cancer Protein Interaction Network. Little is known about the molecular mechanisms related to conformational changes in the family of ARID domains. Thus, we have examined their structural dynamics to enrich the knowledge on this important family of regulatory proteins. In particular, we used an approach that integrates atomistic simulations and methods inspired by graph theory. To relate these properties to protein function we studied both the free and DNA-bound forms. The interaction with DNA not only stabilizes the conformations of the DNA-binding loops, but also strengthens pre-existing paths in the native ARID ensemble for long-range communication to those loops. Residues in helix 5 are identified as critical mediators for intramolecular communication to the DNA-binding regions. In particular, we identified a distal tyrosine that plays a key role in long-range communication to the DNA-binding loops and that is experimentally known to impair DNA-binding. Mutations at this tyrosine and in other residues of helix 5 are also demonstrated, by our approach, to affect the paths of communication to the DNA-binding loops and alter their native dynamics. Overall, our results are in agreement with a scenario in which ARID domains exist as an ensemble of substates, which are shifted by external perturbation, such as the interaction with DNA. Conformational changes at the DNA-binding loops are transmitted long-range by intramolecular paths, which have their heart in helix 5.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
DNA
/
Proteínas de Ligação a DNA
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
PLoS Comput Biol
Assunto da revista:
BIOLOGIA
/
INFORMATICA MEDICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Dinamarca