Catalytic pocket inaccessibility of activation-induced cytidine deaminase is a safeguard against excessive mutagenic activity.
Structure
; 23(4): 615-27, 2015 Apr 07.
Article
en En
| MEDLINE
| ID: mdl-25728927
ABSTRACT
Activation-induced cytidine deaminase (AID) mutates cytidine to uridine at immunoglobulin loci to initiate secondary antibody diversification but also causes genome-wide damage. We previously demonstrated that AID has a relatively low catalytic rate. The structure of AID has not been solved. Thus, to probe the basis for its catalytic lethargy we generated a panel of free or DNA-bound AID models based on eight recently resolved APOBEC structures. Docking revealed that the majority of AIDDNA complexes would be inactive due to substrate binding such that a cytidine is not positioned for deamination. Furthermore, we found that most AID conformations exhibit fully or partially occluded catalytic pockets. We constructed mutant and chimeric AID variants predicted to have altered catalytic pocket accessibility dynamics and observed significant correlation with catalytic rate. Data from modeling simulations and functional tests of AID variants support the notion that catalytic pocket accessibility is an inherent bottleneck for AID activity.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Dominio Catalítico
/
Citidina Desaminasa
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Structure
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Año:
2015
Tipo del documento:
Article