id: O43824 gene_symbol: GTPBP6 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: GTPBP6 (Putative GTP-binding protein 6, PGPL) is a TRAFAC-class OBG-HflX-like GTPase encoded by a pseudoautosomal gene near the Xp/Yp telomere. It functions in mitochondria as one of several conserved GTPases (alongside GTPBP5, GTPBP7 and GTPBP10) that drive late maturation of the mitochondrial large ribosomal subunit (mtLSU). GTPBP6 acts at a final step of mtLSU biogenesis, triggering a molecular switch that drives progression to a near-mature peptidyl transferase centre (PTC), and additionally has a role in recycling/dissociation of mature mitochondrial ribosomes, giving it a dual role in mitoribosome biogenesis and recycling. Its activity is GTP-dependent, consistent with the conserved G-domain motifs of the OBG-HflX-like family. existing_annotations: - term: id: GO:0043022 label: ribosome binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Phylogenetic transfer of ribosome binding from bacterial ObgE/CgtA-like orthologs. GTPBP6 does bind the ribosome, but in human cells the relevant substrate is the mitochondrial large ribosomal subunit rather than the cytoplasmic ribosome. action: KEEP_AS_NON_CORE reason: Ribosome binding is correct at the family level, but the specific, experimentally supported activity is binding the mitochondrial large ribosomal subunit (captured by the IDA GO:0043023 annotation). Retained as a non-core general term. supported_by: - reference_id: PMID:34135319 supporting_text: the GTPases GTPBP5, GTPBP6, GTPBP7, and GTPBP10 mediate mtLSU maturation - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic transfer of cytoplasmic localization from bacterial orthologs. The experimentally characterized human GTPBP6 acts in the mitochondrion on the mitoribosome, so this generic cytoplasmic localization is misleading. action: MARK_AS_OVER_ANNOTATED reason: GTPBP6 localizes to and acts in mitochondria (HTP mitochondrion; mtLSU biogenesis), not the general cytoplasm; the IBA cytoplasm transfer from bacterial orthologs does not reflect the human protein's compartment. supported_by: - reference_id: PMID:34135319 supporting_text: the GTPases GTPBP5, GTPBP6, GTPBP7, and GTPBP10 mediate mtLSU maturation - term: id: GO:0005525 label: GTP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based assignment of GTP binding, consistent with the conserved G-domain motifs of the OBG-HflX-like GTPase family. action: ACCEPT reason: GTPBP6 is a GTPase with canonical G-domain motifs; GTP binding is a core molecular function that underlies its role as a maturation/recycling GTPase. supported_by: - reference_id: file:human/GTPBP6/GTPBP6-uniprot.txt supporting_text: Belongs to the TRAFAC class OBG-HflX-like GTPase - term: id: GO:0043023 label: ribosomal large subunit binding evidence_type: IDA original_reference_id: PMID:34135319 qualifier: enables review: summary: Direct evidence (cryo-EM, in vitro reconstitution) that GTPBP6 binds the mitochondrial large ribosomal subunit during late mtLSU maturation and recycling. action: ACCEPT reason: Direct experimental support for GTPBP6 binding the large (mito)ribosomal subunit; this is a core molecular function. supported_by: - reference_id: PMID:34135319 supporting_text: Addition of recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and shows that GTPBP6 triggers a molecular switch and progression to a near-mature PTC state - term: id: GO:1902775 label: mitochondrial large ribosomal subunit assembly evidence_type: IDA original_reference_id: PMID:34135319 qualifier: involved_in review: summary: Direct evidence that GTPBP6 is required for and drives late assembly/maturation of the mitochondrial large ribosomal subunit (PTC folding), with GTPBP6-deficient cells accumulating late mtLSU intermediates. action: ACCEPT reason: Direct experimental support for GTPBP6's core biological process; this is its principal characterized function. supported_by: - reference_id: PMID:34135319 supporting_text: Structures of transient native mtLSU assembly intermediates that accumulate in GTPBP6-deficient cells reveal how the biogenesis factors GTPBP5, MTERF4 and NSUN4 facilitate PTC folding - term: id: GO:0005739 label: mitochondrion evidence_type: HTP original_reference_id: PMID:34800366 qualifier: located_in review: summary: High-throughput proteomic evidence that GTPBP6 localizes to mitochondria, consistent with its role in mitoribosome biogenesis. action: ACCEPT reason: Mitochondrial localization is the correct compartment for GTPBP6 and is consistent with the mtLSU-maturation function; this should be regarded as the core localization (in preference to the IBA cytoplasm transfer). supported_by: - reference_id: file:human/GTPBP6/GTPBP6-goa.tsv supporting_text: GO:0005739 mitochondrion cellular_component ECO:0006056 HTP PMID:34800366 - term: id: GO:0005525 label: GTP binding evidence_type: TAS original_reference_id: PMID:9466997 qualifier: enables review: summary: The original cloning paper reported the GTP-binding protein domain motifs of PGPL/GTPBP6. action: ACCEPT reason: Author-stated GTP-binding consensus motifs, consistent with the InterPro assignment and the protein's GTPase family; supports the core MF. supported_by: - reference_id: PMID:9466997 supporting_text: shows the consensus sequences of a series of motifs of the GTP-binding protein domain 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: PMID:34135319 title: Structural basis of GTPase-mediated mitochondrial ribosome biogenesis and recycling. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publications/PMID_34135319.md title matches; anchored to GOA as the IDA source for GO:0043023 (ribosomal large subunit binding) and GO:1902775 (mtLSU assembly). Recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro, directly establishing the core function. Cited in core_functions supported_by." findings: - statement: GTPBP6 (with GTPBP5, GTPBP7, GTPBP10) mediates late maturation of the mitochondrial large ribosomal subunit; recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and triggers progression to a near-mature PTC state. reference_section_type: ABSTRACT - statement: GTPBP6 has a dual role in mitochondrial ribosome biogenesis and recycling. reference_section_type: ABSTRACT - id: PMID:34800366 title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. findings: - statement: GTPBP6 is detected as a component of the human mitochondrial proteome. reference_section_type: RESULTS - id: PMID:9466997 title: A novel pseudoautosomal gene encoding a putative GTP-binding protein resides in the vicinity of the Xp/Yp telomere. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: "Cached publications/PMID_9466997.md title matches; anchored to GOA as the TAS source for GO:0005525 (GTP binding). Original PGPL/GTPBP6 cloning and pseudoautosomal characterization, supporting the G-domain/GTP-binding function rather than the mitoribosome-maturation role directly." findings: - statement: PGPL (GTPBP6) is a pseudoautosomal gene encoding a 442-aa protein with consensus GTP-binding protein domain motifs; it escapes X inactivation and has a Y-chromosome homologue. reference_section_type: ABSTRACT core_functions: - description: Mitochondrial OBG-HflX-like GTPase that binds the mitochondrial large ribosomal subunit and uses GTP to drive a late maturation step (PTC folding) of mtLSU biogenesis, and to promote recycling of mature mitochondrial ribosomes. molecular_function: id: GO:0043023 label: ribosomal large subunit binding locations: - id: GO:0005739 label: mitochondrion supported_by: - reference_id: PMID:34135319 supporting_text: Addition of recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and shows that GTPBP6 triggers a molecular switch and progression to a near-mature PTC state - reference_id: PMID:34135319 supporting_text: the GTPases GTPBP5, GTPBP6, GTPBP7, and GTPBP10 mediate mtLSU maturation - description: GTP-binding/GTPase activity of the OBG-HflX-like G-domain that powers GTPBP6's role as a mitoribosome maturation/recycling factor. molecular_function: id: GO:0005525 label: GTP binding locations: - id: GO:0005739 label: mitochondrion supported_by: - reference_id: file:human/GTPBP6/GTPBP6-uniprot.txt supporting_text: Belongs to the TRAFAC class OBG-HflX-like GTPase - reference_id: PMID:9466997 supporting_text: shows the consensus sequences of a series of motifs of the GTP-binding protein domain proposed_new_terms: [] suggested_questions: - question: Does human GTPBP6 have any role on cytoplasmic ribosomes, or is its function exclusively mitochondrial (the IBA cytoplasm transfer derives from bacterial orthologs)? - question: What is the precise GTPase cycle (activating factors, GAP) that couples GTPBP6 nucleotide state to the molecular switch driving PTC maturation? suggested_experiments: - description: Subcellular fractionation and high-resolution imaging of endogenous GTPBP6 to definitively establish mitochondrial localization and exclude a cytoplasmic ribosome-associated pool. - description: GTPase-dead (G-domain mutant) GTPBP6 rescue experiments in GTPBP6-knockout cells to test whether GTP hydrolysis is required for mtLSU maturation versus ribosome recycling.