8jfk
From Proteopedia
PhK holoenzyme in inactive state, muscle isoform
Structural highlights
DiseaseKPBB_HUMAN Glycogen storage disease due to liver and muscle phosphorylase kinase deficiency. The disease is caused by variants affecting the gene represented in this entry. FunctionKPBB_HUMAN Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The beta chain acts as a regulatory unit and modulates the activity of the holoenzyme in response to phosphorylation. Publication Abstract from PubMedThe 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 alpha(4)beta(4)gamma(4)delta(4) hexadecamer consists of a tetramer of tetramer, wherein four alphabetagammadelta modules are connected by the central beta(4) scaffold. The alpha- and beta-subunits possess glucoamylase-like domains, but exhibit no detectable enzyme activities. The alpha-subunit serves as a bridge between the beta-subunit and the gammadelta subcomplex, and facilitates the gamma-subunit to adopt an autoinhibited state. Ca(2+)-free calmodulin (delta-subunit) binds to the gamma-subunit in a compact conformation. Upon binding of Ca(2+), a conformational change occurs, allowing for the de-inhibition of the gamma-subunit through a spring-loaded mechanism. We also reveal an ADP-binding pocket in the beta-subunit, which plays a role in allosterically enhancing PhK activity. These results provide molecular insights of this important kinase complex. Architecture and activation of human muscle phosphorylase kinase.,Yang X, Zhu M, Lu X, Wang Y, Xiao J Nat Commun. 2024 Mar 28;15(1):2719. doi: 10.1038/s41467-024-47049-2. PMID:38548794[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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