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).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005964 phosphorylase kinase complex | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/PHKB/PHKB-uniprot.txt are regulatory subunits, gamma (PHKG1 or PHKG2) is the catalytic PMID:38548794 wherein four Ξ±Ξ²Ξ³Ξ΄ modules are connected by the central Ξ²4 scaffold |
| GO:0005516 calmodulin binding | IEA GO_REF:0000002 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/PHKB/PHKB-uniprot.txt note="Calmodulin-binding" |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/PHKB/PHKB-uniprot.txt Cell membrane {ECO:0000305}; Lipid-anchor |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | MODIFY | 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. 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 replacements: glycogen catabolic process glycogen metabolic process Supporting Evidence: file:human/PHKB/PHKB-uniprot.txt Glycan biosynthesis; glycogen metabolism. |
| GO:0005977 glycogen metabolic process | IEA GO_REF:0000120 | ACCEPT | 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. 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". Supporting Evidence: file:human/PHKB/PHKB-uniprot.txt Glycan biosynthesis; glycogen metabolism. |
| GO:0005515 protein binding | IPI PMID:21418524 Substrate preference and phosphatidylinositol monophosphate ... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:21418524 regulates glycogen synthesis |
| GO:0005515 protein binding | IPI PMID:25051373 KIAA1199 interacts with glycogen phosphorylase kinase Ξ²-subu... | MARK AS OVER ANNOTATED | 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). 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. Supporting Evidence: PMID:25051373 the glycogen phosphorylase kinase Ξ²-subunit (PHKB) interacted with the |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | 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). 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. Supporting Evidence: PMID:25416956 a systematic map of ?14,000 high-quality human |
| GO:0005964 phosphorylase kinase complex | IEA GO_REF:0000107 | ACCEPT | 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. Reason: Redundant with the IBA and ComplexPortal IPI annotations to the same term; the cellular-component assignment is accurate. Supporting Evidence: file:human/PHKB/PHKB-uniprot.txt are regulatory subunits, gamma (PHKG1 or PHKG2) is the catalytic |
| GO:0005964 phosphorylase kinase complex | IPI PMID:38548794 Architecture and activation of human muscle phosphorylase ki... | ACCEPT | 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. Reason: Direct structural evidence (cryo-EM) places PHKB in the phosphorylase kinase holoenzyme as the central scaffolding subunit. Core cellular-component annotation. Supporting Evidence: PMID:38548794 The 1.3-megadalton PhK Ξ±4Ξ²4Ξ³4Ξ΄4 hexadecamer consists of a tetramer of PMID:38548794 wherein four Ξ±Ξ²Ξ³Ξ΄ modules are connected by the central Ξ²4 scaffold |
| GO:0005980 glycogen catabolic process | IDA PMID:38548794 Architecture and activation of human muscle phosphorylase ki... | ACCEPT | 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. 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. Supporting Evidence: PMID:38548794 We also reveal an ADP-binding pocket in the Ξ²-subunit, which plays a PMID:25051373 Glycogen phosphorylase kinase (PHK) is a serine/threonine-specific protein kinase that phosphorylates a serine residue in glycogen phosphorylase (PYG) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-71541 | ACCEPT | 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. 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. Supporting Evidence: Reactome:R-HSA-71541 The cytosolic phosphorylase kinase complex catalyzes the phosphorylation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-71588 | ACCEPT | 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. 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. Supporting Evidence: Reactome:R-HSA-71588 The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL) |
| GO:0005977 glycogen metabolic process | TAS PMID:9402963 Phosphorylase-kinase-deficient liver glycogenosis with an un... | ACCEPT | 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. 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. Supporting Evidence: PMID:9402963 liver glycogenosis caused by Phk deficiency |
| GO:0006091 generation of precursor metabolites and energy | TAS PMID:9402963 Phosphorylase-kinase-deficient liver glycogenosis with an un... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:9402963 liver glycogenosis caused by Phk deficiency |
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