Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis.
Proc Natl Acad Sci U S A
; 103(29): 10961-6, 2006 Jul 18.
Article
en En
| MEDLINE
| ID: mdl-16832055
ABSTRACT
The immunovariant N-ethyl-N-nitrosourea-induced mutations Pococurante (Poc) and Lackadaisical were found to alter MyD88, creating striking receptor-selective effects. Poc, in particular, prevented sensing of all MyD88-dependent Toll-like receptor (TLR) ligands except diacyl lipopeptides. Furthermore, Poc-site and classical BB loop mutations caused equivalent phenotypes when engrafted into any TLR/IL-1 receptor/resistance (TIR) domain. These observations, complemented by data from docking studies and site-directed mutagenesis, revealed that BB loops and Poc sites interact homotypically across the receptoradapter signaling interface, whereas the C-terminal alpha(E)-helices support adapteradapter and receptorreceptor oligomerization. We have thus defined the TIR domain surface that mediates association between TLRs and MyD88 and the surface required for MyD88 or TLR oligomerization. Moreover, MyD88 engages individual TLRs differently, suggesting the feasibility of selective pharmacologic TIR domain receptor blockade.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Mutagénesis
/
Proteínas Adaptadoras Transductoras de Señales
/
Receptores Toll-Like
/
Células Germinativas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos