id: Q93100
gene_symbol: PHKB
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PHKB encodes the beta regulatory subunit of phosphorylase kinase (PhK), a large
  ~1.3 MDa (alpha-beta-gamma-delta)4 hexadecameric enzyme complex that controls
  glycogenolysis. Within the holoenzyme the gamma subunit (PHKG1 in muscle, PHKG2
  in liver) is the catalytic Ser/Thr protein kinase, the alpha (PHKA1/PHKA2) and
  beta (PHKB) subunits are large non-catalytic regulatory subunits, and the delta
  subunit is calmodulin. PHKB is a shared component of both the muscle and liver
  holoenzymes. It forms a central beta4 scaffold that connects the four
  alpha-beta-gamma-delta modules and possesses a glucoamylase-like fold that lacks
  detectable enzyme activity. PHKB is a target of cAMP-dependent protein kinase
  (PKA); phosphorylation of the alpha and beta subunits, together with Ca2+ sensing
  by the delta (calmodulin) subunit, relieves autoinhibition of the catalytic gamma
  subunit, allowing PhK to phosphorylate glycogen phosphorylase (converting it from
  the b to the a form) and thereby trigger glycogen breakdown. PhK is a cytosolic
  enzyme. Loss-of-function mutations in PHKB cause glycogen storage disease type IXb
  (combined liver and muscle phosphorylase kinase deficiency, autosomal recessive,
  generally mild).
alternative_products:
- name: '1'
  id: Q93100-1
- name: '2'
  id: Q93100-2
  sequence_note: VSP_012445
- name: '3'
  id: Q93100-3
  sequence_note: VSP_012446
- name: '4'
  id: Q93100-4
  sequence_note: VSP_012445, VSP_012446
existing_annotations:
- term:
    id: GO:0005964
    label: phosphorylase kinase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: PHKB is the beta subunit of phosphorylase kinase, so it is a constituent
      of the phosphorylase kinase complex. This phylogenetic (IBA) assignment is
      accurate and represents a core cellular-component annotation.
    action: ACCEPT
    reason: PHKB is definitionally a subunit of the (alpha-beta-gamma-delta)4 phosphorylase
      kinase holoenzyme. The IBA propagation is consistent with UniProt SUBUNIT and
      with cryo-EM of the human muscle complex.
    supported_by:
      - reference_id: file:human/PHKB/PHKB-uniprot.txt
        supporting_text: "are regulatory subunits, gamma (PHKG1 or PHKG2) is the catalytic"
      - reference_id: PMID:38548794
        supporting_text: "wherein four αβγδ modules are connected by the central β4 scaffold"
- term:
    id: GO:0005516
    label: calmodulin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based (IEA) calmodulin-binding annotation. UniProt annotates
      three predicted calmodulin-binding regions in PHKB (aa 7-29, 768-795, 920-951;
      ECO:0000255) and carries the Calmodulin-binding keyword. This is plausible but
      is a secondary/inferred activity - the primary calmodulin (delta) subunit of
      PhK binds the catalytic gamma subunit, not PHKB.
    action: KEEP_AS_NON_CORE
    reason: The calmodulin-binding regions of PHKB are computationally predicted
      (ECO:0000255) rather than experimentally demonstrated, and calmodulin sensing
      in PhK is chiefly mediated by the integral delta (calmodulin) subunit acting on
      the gamma subunit. Retain as a plausible non-core molecular function of the
      regulatory beta subunit rather than as its defining function.
    supported_by:
      - reference_id: file:human/PHKB/PHKB-uniprot.txt
        supporting_text: 'note="Calmodulin-binding"'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProtKB-SubCell IEA mapping to plasma membrane, derived from the
      UniProt "Cell membrane; Lipid-anchor; Cytoplasmic side" location. That location
      is itself an ECO:0000305 inference based on predicted C-terminal farnesylation
      (by similarity to rabbit PHKB), not on direct human evidence. Phosphorylase
      kinase is otherwise well established as a cytosolic enzyme.
    action: KEEP_AS_NON_CORE
    reason: The plasma-membrane assignment rests on an inferred lipid anchor
      (farnesylation of the C-terminal cysteine, by similarity), and UniProt itself
      notes uncertainty about the C-terminal processing. The functionally dominant
      localization of the PhK holoenzyme is cytosolic (see the Reactome-based cytosol
      annotations). Keep as a weak, non-core membrane-association annotation.
    supported_by:
      - reference_id: file:human/PHKB/PHKB-uniprot.txt
        supporting_text: "Cell membrane {ECO:0000305}; Lipid-anchor"
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based (IEA) annotation to the broad parent term carbohydrate
      metabolic process. PHKB is a regulatory subunit of phosphorylase kinase, whose
      specific role is the control of glycogen breakdown; a more precise glycogen
      catabolic / glycogen metabolic term better captures its biology.
    action: MODIFY
    reason: The term is correct but too general. PHKB acts specifically in glycogen
      catabolism via the phosphorylase kinase complex; the more specific glycogen
      metabolic / glycogen catabolic process terms (already present as other
      annotations) are preferable.
    proposed_replacement_terms:
      - id: GO:0005980
        label: glycogen catabolic process
      - id: GO:0005977
        label: glycogen metabolic process
    supported_by:
      - reference_id: file:human/PHKB/PHKB-uniprot.txt
        supporting_text: "Glycan biosynthesis; glycogen metabolism."
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: IEA annotation (InterPro + UniPathway) to glycogen metabolic process.
      This accurately reflects PHKB's biological role as a regulatory subunit of the
      phosphorylase kinase complex that controls glycogen breakdown, and matches the
      UniProt pathway assignment.
    action: ACCEPT
    reason: Glycogen metabolic process correctly describes the biological role of
      PHKB. It is corroborated by an independent TAS annotation to the same term
      (PMID:9402963) and by the UniProt pathway "Glycan biosynthesis; glycogen
      metabolism".
    supported_by:
      - reference_id: file:human/PHKB/PHKB-uniprot.txt
        supporting_text: "Glycan biosynthesis; glycogen metabolism."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21418524
  qualifier: enables
  review:
    summary: IntAct IPI protein-binding annotation, interactant PASK/PASKIN (Q96RG2).
      The cited paper concerns PASKIN substrate preference and phosphatidylinositol
      inhibition; PHKB is recorded only as a high-throughput binary interactant. The
      bare protein binding term (GO:0005515) conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare protein binding (GO:0005515) is uninformative and is discouraged as
      a molecular-function annotation. The interaction is not the subject of this
      paper and no informative function follows from it, so it is retained but flagged
      as an over-annotation rather than removed."
    supported_by:
      - reference_id: PMID:21418524
        supporting_text: "regulates glycogen synthesis"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25051373
  qualifier: enables
  review:
    summary: IntAct IPI protein-binding annotation, interactant CEMIP/KIAA1199
      (Q8WUJ3). Pull-down and co-immunoprecipitation showed PHKB binds the C-terminal
      region of KIAA1199, proposed to promote glycogen breakdown and cancer-cell
      survival. Although this is real interaction evidence, the annotated term is the
      uninformative bare protein binding (GO:0005515).
    action: MARK_AS_OVER_ANNOTATED
    reason: "The binding is experimentally supported, but the GO:0005515 protein
      binding term captures no specific molecular function and is discouraged. The
      biologically meaningful role (regulation of glycogen breakdown via the
      phosphorylase kinase complex) is captured by the process/complex annotations, so
      this bare-binding term is flagged as an over-annotation and retained."
    supported_by:
      - reference_id: PMID:25051373
        supporting_text: "the glycogen phosphorylase kinase β-subunit (PHKB) interacted with the"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: IntAct IPI protein-binding annotation, interactant CAMK2B (Q13554), from
      a proteome-scale binary interactome map. PHKB is one of ~14,000 systematically
      screened interactions. The annotated term is the uninformative bare protein
      binding (GO:0005515).
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare protein binding (GO:0005515) from a high-throughput interactome
      screen provides no specific molecular-function information and is discouraged.
      Retained but flagged as an over-annotation."
    supported_by:
      - reference_id: PMID:25416956
        supporting_text: "a systematic map of ?14,000 high-quality human"
- term:
    id: GO:0005964
    label: phosphorylase kinase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Ensembl-Compara ortholog-transfer (IEA) annotation to phosphorylase
      kinase complex, duplicating the IBA and IPI assignments. Correct and consistent
      with PHKB being a defining subunit of the holoenzyme.
    action: ACCEPT
    reason: Redundant with the IBA and ComplexPortal IPI annotations to the same term;
      the cellular-component assignment is accurate.
    supported_by:
      - reference_id: file:human/PHKB/PHKB-uniprot.txt
        supporting_text: "are regulatory subunits, gamma (PHKG1 or PHKG2) is the catalytic"
- term:
    id: GO:0005964
    label: phosphorylase kinase complex
  evidence_type: IPI
  original_reference_id: PMID:38548794
  qualifier: part_of
  review:
    summary: ComplexPortal IPI annotation to phosphorylase kinase complex, based on
      the cryo-EM structure of human muscle PhK, which resolves the beta subunit
      forming the central beta4 scaffold that connects the four alpha-beta-gamma-delta
      modules of the 1.3 MDa hexadecamer. This is strong, structure-based evidence for
      PHKB as a core component of the complex.
    action: ACCEPT
    reason: Direct structural evidence (cryo-EM) places PHKB in the phosphorylase
      kinase holoenzyme as the central scaffolding subunit. Core cellular-component
      annotation.
    supported_by:
      - reference_id: PMID:38548794
        supporting_text: "The 1.3-megadalton PhK α4β4γ4δ4 hexadecamer consists of a tetramer of"
      - reference_id: PMID:38548794
        supporting_text: "wherein four αβγδ modules are connected by the central β4 scaffold"
- term:
    id: GO:0005980
    label: glycogen catabolic process
  evidence_type: IDA
  original_reference_id: PMID:38548794
  qualifier: involved_in
  review:
    summary: ComplexPortal IDA annotation to glycogen catabolic process. As a subunit
      of phosphorylase kinase, PHKB participates in the activation of glycogen
      phosphorylase and thereby in glycogen breakdown. The cryo-EM study shows the
      beta subunit both scaffolds the complex and, via its ADP-binding pocket,
      allosterically enhances PhK activity. This is the core biological process for
      the gene.
    action: ACCEPT
    reason: PHKB is a regulatory subunit of the kinase that triggers glycogenolysis;
      glycogen catabolic process accurately and specifically captures its core
      biological role. The beta subunit contributes to the process not only
      structurally but through an allosteric ADP-binding pocket that enhances activity.
    supported_by:
      - reference_id: PMID:38548794
        supporting_text: "We also reveal an ADP-binding pocket in the β-subunit, which plays a"
      - reference_id: PMID:25051373
        supporting_text: "Glycogen phosphorylase kinase (PHK) is a serine/threonine-specific protein kinase that phosphorylates a serine residue in glycogen phosphorylase (PYG)"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71541
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing PHKB in the cytosol, from the muscle
      phosphorylase kinase reaction (PYGM phosphorylation). Phosphorylase kinase is a
      cytosolic enzyme, and this is a core, accurate localization for the complex.
    action: ACCEPT
    reason: The phosphorylase kinase complex acts in the cytosol where it phosphorylates
      cytosolic glycogen phosphorylase; cytosol is the functionally dominant
      localization and is well supported by Reactome.
    supported_by:
      - reference_id: Reactome:R-HSA-71541
        supporting_text: "The cytosolic phosphorylase kinase complex catalyzes the phosphorylation"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71588
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing PHKB in the cytosol, from the liver
      phosphorylase kinase reaction (PYGL phosphorylation). This is the liver-variant
      holoenzyme (PHKA2/PHKB/PHKG2/calmodulin) in which PHKB is a shared subunit.
      Cytosol is a core, accurate localization for the complex.
    action: ACCEPT
    reason: Duplicates the cytosol assignment from the muscle-variant reaction and is
      equally accurate; PHKB is the shared beta subunit of both the muscle and liver
      cytosolic holoenzymes.
    supported_by:
      - reference_id: Reactome:R-HSA-71588
        supporting_text: "The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL)"
- term:
    id: GO:0005977
    label: glycogen metabolic process
  evidence_type: TAS
  original_reference_id: PMID:9402963
  qualifier: involved_in
  review:
    summary: TAS annotation to glycogen metabolic process, from a study identifying a
      PHKB missense mutation (plus a splice-site mutation) causing phosphorylase
      kinase-deficient liver glycogenosis. Loss of PHKB function impairs glycogen
      breakdown, confirming PHKB's role in glycogen metabolism.
    action: ACCEPT
    reason: Human genetic evidence (PHKB mutations causing phosphorylase kinase
      deficiency / liver glycogenosis) directly supports involvement in glycogen
      metabolism. Consistent with the IEA annotation to the same term.
    supported_by:
      - reference_id: PMID:9402963
        supporting_text: "liver glycogenosis caused by Phk deficiency"
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: TAS
  original_reference_id: PMID:9402963
  qualifier: involved_in
  review:
    summary: TAS annotation to generation of precursor metabolites and energy. This
      is a broad parent process; glycogenolysis driven by phosphorylase kinase does
      mobilize glucose (glucose-1-phosphate) for energy, but the term is much less
      specific than the glycogen catabolic / glycogen metabolic annotations and does
      not describe the distinctive function of PHKB.
    action: KEEP_AS_NON_CORE
    reason: The term is not wrong - glycogen breakdown ultimately supplies glucose for
      energy production - but it is high-level and generic. The specific glycogen
      catabolic/metabolic annotations better capture PHKB's role, so this broad energy
      term is retained as non-core.
    supported_by:
      - reference_id: PMID:9402963
        supporting_text: "liver glycogenosis caused by Phk deficiency"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:21418524
  title: Substrate preference and phosphatidylinositol monophosphate inhibition of
    the catalytic domain of the Per-Arnt-Sim domain kinase PASKIN.
  findings: []
- id: PMID:25051373
  title: KIAA1199 interacts with glycogen phosphorylase kinase β-subunit (PHKB) to
    promote glycogen breakdown and cancer cell survival.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:38548794
  title: Architecture and activation of human muscle phosphorylase kinase.
  findings: []
- id: PMID:9402963
  title: Phosphorylase-kinase-deficient liver glycogenosis with an unusual biochemical
    phenotype in blood cells associated with a missense mutation in the beta subunit
    gene (PHKB).
  findings: []
- id: Reactome:R-HSA-71541
  title: glycogen phosphorylase (PYGM) dimer b + 2 ATP => glycogen phosphorylase (PYGM)
    dimer a + 2 ADP
  findings: []
- id: Reactome:R-HSA-71588
  title: glycogen phosphorylase (PYGL) dimer b + 2 ATP => glycogen phosphorylase (PYGL)
    dimer a + 2 ADP
  findings: []
- id: file:human/PHKB/PHKB-uniprot.txt
  title: UniProtKB Q93100 (KPBB_HUMAN) - Phosphorylase b kinase regulatory subunit beta
  findings: []
core_functions:
- description: Non-catalytic beta regulatory subunit of phosphorylase kinase; forms
    the central beta4 scaffold of the (alpha-beta-gamma-delta)4 holoenzyme and, as a
    PKA-phosphorylation target together with the alpha subunit and the calmodulin
    (delta) sensor, relieves autoinhibition of the catalytic gamma subunit, thereby
    contributing to the phosphorylase kinase activity of the assembled complex.
  supported_by:
    - reference_id: PMID:25051373
      supporting_text: "cAMP levels that stimulate protein kinase A (PKA) to phosphorylate the α- and β-subunits (PHKA and PHKB)"
    - reference_id: file:human/PHKB/PHKB-uniprot.txt
      supporting_text: "as a regulatory unit and modulates the activity of the holoenzyme in"
  molecular_function:
    id: GO:0005516
    label: calmodulin binding
  contributes_to_molecular_function:
    id: GO:0004689
    label: phosphorylase kinase activity
  in_complex:
    id: GO:0005964
    label: phosphorylase kinase complex
  directly_involved_in:
    - id: GO:0005980
      label: glycogen catabolic process
  locations:
    - id: GO:0005829
      label: cytosol