CaMKII binds both substrates and activators at the active site.
Cell Rep
; 40(2): 111064, 2022 07 12.
Article
em En
| MEDLINE
| ID: mdl-35830796
ABSTRACT
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a signaling protein required for long-term memory. When activated by Ca2+/CaM, it sustains activity even after the Ca2+ dissipates. In addition to the well-known autophosphorylation-mediated mechanism, interaction with specific binding partners also persistently activates CaMKII. A long-standing model invokes two distinct S and T sites. If an interactor binds at the T-site, then it will preclude autoinhibition and allow substrates to be phosphorylated at the S site. Here, we specifically test this model with X-ray crystallography, molecular dynamics simulations, and biochemistry. Our data are inconsistent with this model. Co-crystal structures of four different activators or substrates show that they all bind to a single continuous site across the kinase domain. We propose a mechanistic model where persistent CaMKII activity is facilitated by high-affinity binding partners that kinetically compete with autoinhibition by the regulatory segment to allow substrate phosphorylation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Processamento de Proteína Pós-Traducional
/
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos