Architecture and activation of human muscle phosphorylase kinase

Xiaoke Yang, Mingqi Zhu, Xue Lu, Yuxin Wang and Junyu Xiao ()
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Xiaoke Yang: Peking University
Mingqi Zhu: Peking University
Xue Lu: Changping Laboratory
Yuxin Wang: Peking University
Junyu Xiao: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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 α4β4γ4δ4 hexadecamer consists of a tetramer of tetramer, wherein four αβγδ modules are connected by the central β4 scaffold. The α- and β-subunits possess glucoamylase-like domains, but exhibit no detectable enzyme activities. The α-subunit serves as a bridge between the β-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 β-subunit, which plays a role in allosterically enhancing PhK activity. These results provide molecular insights of this important kinase complex.

Date: 2024
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DOI: 10.1038/s41467-024-47049-2

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