Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6.
Elife
; 3: e01998, 2014 Mar 18.
Article
em En
| MEDLINE
| ID: mdl-24642411
ABSTRACT
Glycogen synthase kinase-3 (GSK-3) is a key regulator of many cellular signaling pathways. Unlike most kinases, GSK-3 is controlled by inhibition rather than by specific activation. In the insulin and several other signaling pathways, phosphorylation of a serine present in a conserved sequence near the amino terminus of GSK-3 generates an auto-inhibitory peptide. In contrast, Wnt/ß-catenin signal transduction requires phosphorylation of Ser/Pro rich sequences present in the Wnt co-receptors LRP5/6, and these motifs inhibit GSK-3 activity. We present crystal structures of GSK-3 bound to its phosphorylated N-terminus and to two of the phosphorylated LRP6 motifs. A conserved loop unique to GSK-3 undergoes a dramatic conformational change that clamps the bound pseudo-substrate peptides, and reveals the mechanism of primed substrate recognition. The structures rationalize target sequence preferences and suggest avenues for the design of inhibitors selective for a subset of pathways regulated by GSK-3. DOI http//dx.doi.org/10.7554/eLife.01998.001.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinase 3 da Glicogênio Sintase
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Elife
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos