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- PDB-8xya: hPhK alpha-beta-gamma-delta subcomplex in inactive state -

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Basic information

Entry
Database: PDB / ID: 8xya
TitlehPhK alpha-beta-gamma-delta subcomplex in inactive state
Components
  • Calmodulin-1
  • Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform
  • Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform
  • Phosphorylase b kinase regulatory subunit beta
KeywordsCYTOSOLIC PROTEIN / glycogen phosphorylase b kinase / alpha-beta-gamma-delta subcomplex / muscle isoform / inactive state
Function / homology
Function and homology information


phosphorylase kinase / phosphorylase kinase activity / phosphorylase kinase complex / positive regulation of glycogen catabolic process / tau-protein kinase / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels ...phosphorylase kinase / phosphorylase kinase activity / phosphorylase kinase complex / positive regulation of glycogen catabolic process / tau-protein kinase / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / positive regulation of cyclic-nucleotide phosphodiesterase activity / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / autophagosome membrane docking / mitochondrion-endoplasmic reticulum membrane tethering / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / regulation of cardiac muscle cell action potential / tau-protein kinase activity / glycogen metabolic process / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / Synthesis of IP3 and IP4 in the cytosol / negative regulation of peptidyl-threonine phosphorylation / Negative regulation of NMDA receptor-mediated neuronal transmission / Phase 0 - rapid depolarisation / Unblocking of NMDA receptors, glutamate binding and activation / negative regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / RHO GTPases activate PAKs / Ion transport by P-type ATPases / : / Uptake and function of anthrax toxins / Long-term potentiation / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / catalytic complex / DARPP-32 events / detection of calcium ion / regulation of cardiac muscle contraction / Smooth Muscle Contraction / regulation of ryanodine-sensitive calcium-release channel activity / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / calcium channel inhibitor activity / cellular response to interferon-beta / eNOS activation / Protein methylation / voltage-gated potassium channel complex / Activation of AMPK downstream of NMDARs / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Ion homeostasis / : / titin binding / positive regulation of protein autophosphorylation / regulation of calcium-mediated signaling / sperm midpiece / calcium channel complex / substantia nigra development / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / sarcomere / FCERI mediated Ca+2 mobilization / protein serine/threonine kinase activator activity / FCGR3A-mediated IL10 synthesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated vascular permeability / regulation of cytokinesis / VEGFR2 mediated cell proliferation / positive regulation of peptidyl-threonine phosphorylation / generation of precursor metabolites and energy / spindle microtubule / Translocation of SLC2A4 (GLUT4) to the plasma membrane / positive regulation of receptor signaling pathway via JAK-STAT / RAF activation / Transcriptional activation of mitochondrial biogenesis / positive regulation of protein serine/threonine kinase activity / Stimuli-sensing channels / cellular response to type II interferon / spindle pole / response to calcium ion / RAS processing / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / calcium-dependent protein binding / G2/M transition of mitotic cell cycle / Signaling by BRAF and RAF1 fusions / Inactivation, recovery and regulation of the phototransduction cascade
Similarity search - Function
Phosphorylase kinase alpha/beta subunit / Phosphorylase b kinase regulatory subunit alpha/beta, C-terminal domain / Phosphorylase b kinase C-terminal domain / Phosphorylase kinase, gamma catalytic subunit / GH15-like domain / Glycosyl hydrolases family 15 / Six-hairpin glycosidase-like superfamily / Six-hairpin glycosidase superfamily / : / EF-hand domain pair ...Phosphorylase kinase alpha/beta subunit / Phosphorylase b kinase regulatory subunit alpha/beta, C-terminal domain / Phosphorylase b kinase C-terminal domain / Phosphorylase kinase, gamma catalytic subunit / GH15-like domain / Glycosyl hydrolases family 15 / Six-hairpin glycosidase-like superfamily / Six-hairpin glycosidase superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
FARNESYL / Calmodulin-1 / Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform / Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform / Phosphorylase b kinase regulatory subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsYang, X.K. / Xiao, J.Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Architecture and activation of human muscle phosphorylase kinase.
Authors: Xiaoke Yang / Mingqi Zhu / Xue Lu / Yuxin Wang / Junyu Xiao /
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 ...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 αβγδ hexadecamer consists of a tetramer of tetramer, wherein four αβγδ modules are connected by the central β 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. Ca-free calmodulin (δ-subunit) binds to the γ-subunit in a compact conformation. Upon binding of Ca, 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.
History
DepositionJan 19, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform
B: Phosphorylase b kinase regulatory subunit beta
D: Calmodulin-1
C: Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)324,8526
Polymers324,4404
Non-polymers4132
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform / Phosphorylase kinase alpha M subunit


Mass: 137469.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PHKA1, PHKA / Production host: Homo sapiens (human) / References: UniProt: P46020
#2: Protein Phosphorylase b kinase regulatory subunit beta / Phosphorylase kinase subunit beta


Mass: 125032.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PHKB / Production host: Homo sapiens (human) / References: UniProt: Q93100
#3: Protein Calmodulin-1


Mass: 16852.545 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Homo sapiens (human) / References: UniProt: P0DP23
#4: Protein Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform / PHK-gamma-M / Phosphorylase kinase subunit gamma-1 / Serine/threonine-protein kinase PHKG1


Mass: 45084.672 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PHKG1, PHKG / Production host: Homo sapiens (human)
References: UniProt: Q16816, phosphorylase kinase, non-specific serine/threonine protein kinase, tau-protein kinase
#5: Chemical ChemComp-FAR / FARNESYL


Mass: 206.367 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H26 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: alpha-beta-gamma-delta subcomplex of human phosphorylase b kinase, muscle isoform
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 6.8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: OTHER / Nominal defocus max: 1500 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 1.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 623973 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00482964
ELECTRON MICROSCOPYf_angle_d0.944112286
ELECTRON MICROSCOPYf_dihedral_angle_d5.84511106
ELECTRON MICROSCOPYf_chiral_restr0.04512485
ELECTRON MICROSCOPYf_plane_restr0.00714477

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