Architecture and activation of human muscle phosphorylase kinase.
Nat Commun
; 15(1): 2719, 2024 Mar 28.
Article
em En
| MEDLINE
| ID: mdl-38548794
ABSTRACT
The study of phosphorylase kinase (PhK)-regulated glycogen metabolism has contributed to the fundamental understanding of protein phosphorylation; however, the molecular mechanism of PhK remains poorly understood. Here we present the high-resolution cryo-electron microscopy structures of human muscle PhK. The 1.3-megadalton PhK α4ß4γ4δ4 hexadecamer consists of a tetramer of tetramer, wherein four αßγδ modules are connected by the central ß4 scaffold. The α- and ß-subunits possess glucoamylase-like domains, but exhibit no detectable enzyme activities. The α-subunit serves as a bridge between the ß-subunit and the γδ subcomplex, and facilitates the γ-subunit to adopt an autoinhibited state. Ca2+-free calmodulin (δ-subunit) binds to the γ-subunit in a compact conformation. Upon binding of Ca2+, a conformational change occurs, allowing for the de-inhibition of the γ-subunit through a spring-loaded mechanism. We also reveal an ADP-binding pocket in the ß-subunit, which plays a role in allosterically enhancing PhK activity. These results provide molecular insights of this important kinase complex.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosforilase Quinase
/
Músculos
Limite:
Humans
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2024
Tipo de documento:
Article