HSPA9 (mortalin/GRP75/mtHsp70/PBP74) is the human mitochondrial Hsp70-family ATP-dependent chaperone (EC 3.6.4.10). Synthesized in the cytosol with an N-terminal mitochondrial targeting sequence and matured in the mitochondrial matrix, it functions as the core ATPase motor of the presequence translocase-associated motor (PAM) that drives import and folding of nuclear-encoded matrix proteins through the TIM23 complex. Mortalin also acts in mitochondrial iron-sulfur cluster biogenesis where, with its J-protein cochaperone HSC20/HSCB, it delivers nascent Fe-S clusters from the ISCU scaffold to client apoproteins, and contributes to general protein quality control through ATP-driven cycles of substrate binding/release coordinated by mitochondrial J-domain co-chaperones (Tim14/DNAJC15/19, Tim16/Magmas) and nucleotide-exchange factors (GRPEL1/2). Pathogenic HSPA9 variants cause autosomal recessive sideroblastic anemia 4 (SIDBA4) and EVEN-PLUS syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cytoplasm localization by phylogenetic inference. HSPA9 is synthesized in the cytosol as a precursor with a cleavable mitochondrial targeting sequence and is imported into the mitochondrial matrix, where it performs its function. A transient cytosolic precursor pool exists, and stress-induced extramitochondrial pools have been reported, so this broad localization is not wrong, but it is non-core relative to the matrix/inner-membrane site of action. Reason: The dominant, functionally relevant localization is the mitochondrial matrix/inner membrane, not the cytoplasm. The cytoplasmic pool is largely the transient precursor plus reported stress-induced extramitochondrial redistribution; keep as non-core. Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md HSPA9 predominantly resides in the mitochondrial matrix where it supports protein import and proteostasis; reviews describe an N-terminal targeting sequence |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrion localization by phylogenetic inference. HSPA9/mortalin is a well-established mitochondrial Hsp70 that resides in the matrix and is associated with the inner membrane import machinery. This is strongly supported across orthologs and by direct human studies. Reason: HSPA9 is a canonical mitochondrial protein; the IBA mitochondrion call is correct and consistent with experimental localization data (PMID:7865888, PMID:7829505) and the mitochondrial proteome (PMID:34800366). Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATP hydrolysis activity by phylogenetic inference. As an Hsp70-family chaperone, HSPA9 hydrolyzes ATP at its N-terminal nucleotide-binding domain (EC 3.6.4.10) to power substrate binding/release cycling. This is directly demonstrated biochemically for human mortalin. Reason: Core catalytic activity of HSPA9, confirmed by direct biochemical assays of human mortalin ATPase activity (PMID:18632665, PMID:25615450) and conserved across the Hsp70 family. Supporting Evidence: PMID:18632665 The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis. |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: Heat shock protein binding by phylogenetic inference. Hsp70 chaperones engage co-chaperones and partner Hsp proteins (e.g., J-domain proteins, escort protein Hep/DNLZ) as part of their functional cycle. HSPA9 specifically binds the Hep/DNLZ escort protein and DNAJ co-chaperones. Reason: Consistent with Hsp70 biology and supported by direct evidence that HSPA9 binds its escort/co-chaperone partners (PMID:18632665). The term reflects a genuine, mechanistically relevant binding activity rather than bare protein binding. Supporting Evidence: PMID:18632665 The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis. |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | ACCEPT | Summary: Protein folding chaperone activity by phylogenetic inference. This is the central molecular function of HSPA9/mortalin as the mitochondrial Hsp70 foldase, driving ATP-dependent folding/refolding of matrix client proteins and supplying the motor force for import-coupled folding. Reason: This is the core molecular function of HSPA9 and is well supported across orthologs and by human biochemical characterization (PMID:25615450). It is the preferred, mechanistically informative MF term and the target of MODIFY for the generic GO:0051082 annotations. Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70. |
| GO:0016226 iron-sulfur cluster assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Iron-sulfur cluster assembly by phylogenetic inference. HSPA9/mortalin is the dedicated mitochondrial Hsp70 that, with its J-protein co-chaperone HSC20/HSCB, drives ATP-dependent transfer of nascent Fe-S clusters from the ISCU scaffold to recipient apoproteins. This conserved function is supported by direct human studies. Reason: A core, well-supported biological process for HSPA9. The IBA call is consistent with direct human experimental evidence (PMID:23940031, PMID:26702583, PMID:28380382) showing HSPA9 acts on ISCU conformational states during Fe-S cluster delivery. Supporting Evidence: PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU). |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | ACCEPT | Summary: Protein refolding by phylogenetic inference. As the mitochondrial Hsp70 foldase, HSPA9 drives ATP-dependent refolding of misfolded/stress-denatured matrix proteins, a conserved Hsp70 activity. Reason: Consistent with the canonical mitochondrial Hsp70 chaperone role and supported across orthologs; refolding of denatured matrix clients is a genuine HSPA9 process aspect complementary to the GO:0044183 molecular function. Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: Nucleotide binding from UniProt keyword mapping. HSPA9 binds adenine nucleotides at its N-terminal nucleotide-binding domain. This is a correct but very general molecular function term; the more specific ATP binding (GO:0005524) is also annotated. Reason: Correct based on the conserved Hsp70 ATPase domain and direct biochemical demonstration of adenine-nucleotide binding by human mortalin (PMID:25615450). It is broad but not wrong; the more specific ATP binding term is retained alongside it. Supporting Evidence: PMID:25615450 Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: ATP binding inferred from InterPro/keyword mapping. HSPA9 binds ATP at its nucleotide-binding domain as the obligatory first step of the Hsp70 chaperone cycle, directly demonstrated for human mortalin. Reason: Accurate and appropriately specific molecular function for an Hsp70 ATPase; confirmed by biochemical characterization of human mortalin nucleotide binding (PMID:25615450). Supporting Evidence: PMID:25615450 Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization. |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: Nucleolus localization mapped from a UniProt subcellular-location keyword. Reports of mortalin in the nucleus/nucleolus exist but are minor relative to its dominant mitochondrial matrix localization, and the term is derived from automated keyword mapping rather than focused experimental evidence. Reason: HSPA9 is an imported mitochondrial matrix chaperone; nucleolar localization is at best a minor, context-dependent extramitochondrial pool and not a site where its core function is exercised. The IEA keyword-mapped term over-states this localization. Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md HSPA9 predominantly resides in the mitochondrial matrix where it supports protein import and proteostasis; reviews describe an N-terminal targeting sequence |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasm localization mapped from a UniProt subcellular-location keyword. A transient cytosolic precursor pool exists prior to mitochondrial import, and stress-induced extramitochondrial redistribution is reported, so the term is not wrong but is non-core relative to the matrix site of action. Reason: Duplicate localization of the IBA cytoplasm call; the functionally relevant site is the mitochondrial matrix/inner membrane. Keep as non-core. Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md Mortalin can redistribute beyond mitochondria (including plasma membrane accumulation) under certain stresses |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrion localization from automated IEA pipelines. HSPA9 is a canonical mitochondrial protein; this is correct though more specific matrix/inner-membrane terms are also annotated. Reason: Correct localization, consistent with all experimental evidence and the mitochondrial proteome (PMID:34800366). Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial matrix localization from automated IEA pipelines. This is the primary, functionally relevant compartment for HSPA9, where it acts as a foldase and as the matrix-side motor of the PAM import machinery. Reason: Accurate and appropriately specific; matches direct IDA localization to the matrix (PMID:7865888) and is the core site of HSPA9 function. Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0006457 protein folding | IEA GO_REF:0000002 | ACCEPT | Summary: Protein folding inferred from InterPro HSP70 family membership. This is a genuine core process for HSPA9 as the mitochondrial Hsp70 foldase. Reason: Correct process annotation consistent with the Hsp70 chaperone mechanism and the directly_involved_in process of the GO:0044183 core function. Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | MODIFY | Summary: Generic hydrolase activity from a UniProt keyword mapping. HSPA9 is an ATP hydrolase (EC 3.6.4.10), but this is a very high-level parent of the more informative ATP hydrolysis activity (GO:0016887) that is also annotated. Reason: GO:0016787 is uninformatively broad. The specific molecular function is ATP hydrolysis activity, already present in the annotation set with experimental support. Proposed replacements: ATP hydrolysis activity Supporting Evidence: PMID:18632665 The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: ATP hydrolysis activity inferred from InterPro HSP70 ATPase domain. This is the core catalytic activity of HSPA9 and is also directly demonstrated experimentally. Reason: Correct and appropriately specific; duplicate of the IBA/IDA ATP hydrolysis calls, all consistent with direct biochemical assays of human mortalin (PMID:18632665, PMID:25615450). Supporting Evidence: PMID:18632665 The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis. |
| GO:0051082 unfolded protein binding | IEA GO_REF:0000002 | MODIFY | Summary: GO:0051082 captures substrate binding but not the mechanistically informative chaperone activity. HSPA9 (mortalin/mtHsp70) is a canonical ATP-dependent mitochondrial Hsp70 chaperone involved in import-associated folding and refolding. GO:0044183 better represents this molecular function. Reason: HSPA9 should be represented as a protein folding chaperone rather than generic unfolded-protein binding. The existing HSPA9 annotation set already includes GO:0044183 and chaperone/refolding process terms, consistent with mtHsp70 biology. Proposed replacements: protein folding chaperone Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70. It belongs to the Hsp70 family, with canonical N-terminal ATPase and C-terminal substrate-binding domains typical of Hsp70s. |
| GO:0005515 protein binding | IPI PMID:15657067 Phosphotyrosine signaling networks in epidermal growth facto... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a high-throughput phosphotyrosine-signaling proteomics screen in EGFR-overexpressing carcinoma cells (interactor EGFR/P00533). This is an uninformative molecular function term from a large-scale dataset, not a mechanistic characterization of HSPA9 function. Reason: GO:0005515 is uninformative and this is a non-specific high-throughput co-occurrence in an EGFR proteomics dataset; it does not represent a core or mechanistically meaningful HSPA9 function. Supporting Evidence: PMID:15657067 Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells. |
| GO:0005515 protein binding | IPI PMID:17184779 Identification of differential proteins in nasopharyngeal ca... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor p53/P04637) derived from a differential proteomics study of p53-silenced nasopharyngeal carcinoma cells. The mortalin-p53 interaction is genuine and important, but this particular evidence is an indirect abundance-change proteomics readout and the MF term itself is uninformative. Reason: GO:0005515 is an uninformative term; the mechanistically relevant HSPA9-p53 interaction is better supported by the direct reconstitution study (PMID:20153329). This proteomics-based entry adds no functional specificity. Supporting Evidence: PMID:17184779 Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis. |
| GO:0005515 protein binding | IPI PMID:20029029 Regulation of epidermal growth factor receptor trafficking b... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor EGFR/P00533) from an EGFR-trafficking interactome study. Uninformative MF term from a large-scale dataset. Reason: GO:0005515 is uninformative; HSPA9 appearance in an EGFR/HDAC6 trafficking dataset does not define a specific molecular function and is not core. Supporting Evidence: PMID:20029029 Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. |
| GO:0005515 protein binding | IPI PMID:20153329 Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 int... | KEEP AS NON CORE | Summary: Bare 'protein binding' representing the direct HSPA9 (mortalin)-p53 interaction, here reconstituted with purified proteins. This is a genuine, mechanistically meaningful interaction underlying mortalin's anti-apoptotic cytosolic sequestration of p53, but the GO term itself is uninformative. Reason: The mortalin-p53 interaction is real and biologically significant (p53 sequestration), but 'protein binding' is an uninformative MF and the p53-related role is a non-core, context-dependent extramitochondrial activity rather than HSPA9's core chaperone/import/Fe-S function. Retain as non-core documentation of the interaction. Supporting Evidence: PMID:20153329 Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins--identification of additional interacting regions. |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a large-scale interacting-protein-regions resource (interactor NELFB/Q8WX92). High-throughput, uninformative MF term. Reason: GO:0005515 is uninformative and this is a non-specific high-throughput interaction-network hit, not a defined HSPA9 function. Supporting Evidence: PMID:20195357 A comprehensive resource of interacting protein regions for refining human transcription factor networks. |
| GO:0005515 protein binding | IPI PMID:22340593 Aurora kinase-A inactivates DNA damage-induced apoptosis and... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactors p73/O15350 and p53/P04637) reported in a study of Aurora kinase-A regulation of p73. Uninformative MF term from a broad interaction dataset. Reason: GO:0005515 is uninformative; the p53/p73-family interactions are peripheral to HSPA9's core function and captured here only as non-specific binding. Supporting Evidence: PMID:22340593 Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73. |
| GO:0005515 protein binding | IPI PMID:22726440 p53 opens the mitochondrial permeability transition pore to ... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor p53/P04637) from a study where mortalin-p53 interaction modulates the mitochondrial permeability transition pore and necrosis. Biologically meaningful interaction but uninformative MF term. Reason: GO:0005515 is uninformative; the mortalin-p53 axis is better captured elsewhere (PMID:20153329) and the necrosis/mPTP role is a downstream consequence, not a defined molecular function of HSPA9. Supporting Evidence: PMID:22726440 p53 opens the mitochondrial permeability transition pore to trigger necrosis. |
| GO:0005515 protein binding | IPI PMID:24189400 Perturbation of the mutated EGFR interactome identifies vuln... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor EGFR/P00533) from a mutant-EGFR interactome perturbation study. High-throughput, uninformative MF term. Reason: GO:0005515 is uninformative and this is a non-specific interactome hit, not a defined HSPA9 function. Supporting Evidence: PMID:24189400 Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms. |
| GO:0005515 protein binding | IPI PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iro... | KEEP AS NON CORE | Summary: Bare 'protein binding' representing the HSPA9-HSC20/HSCB (Q8IWL3) co-chaperone interaction central to Fe-S cluster delivery, where HSC20 recognizes LYR motifs on client/acceptor proteins. The interaction is mechanistically core to Fe-S biogenesis, but the GO term itself is uninformative. Reason: The HSPA9-HSC20 interaction is a genuine, mechanistically important part of Fe-S cluster delivery (captured functionally by GO:0016226 and GO:0044183), but 'protein binding' is uninformative as a standalone MF. Retain as non-core documentation of the co-chaperone partnership. Supporting Evidence: PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a proteome-scale binary interactome map (interactor A4D2J0). High-throughput Y2H-type hit, uninformative MF term. Reason: GO:0005515 is uninformative and this is a non-specific large-scale interactome entry. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from an inter-species interaction-network screen (interactors P38340, P53051). High-throughput, uninformative MF term. Reason: GO:0005515 is uninformative and this is a non-specific large-scale interactome hit. Supporting Evidence: PMID:27107014 An inter-species protein-protein interaction network across vast evolutionary distance. |
| GO:0005515 protein binding | IPI PMID:27607350 Characterization of the Translationally Controlled Tumor Pro... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor TPT1/TCTP, P13693) from a TCTP interactome study in cancer cells. High-throughput, uninformative MF term. Reason: GO:0005515 is uninformative and this interactome co-occurrence does not define a specific HSPA9 function. Supporting Evidence: PMID:27607350 Characterization of the Translationally Controlled Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells. |
| GO:0005515 protein binding | IPI PMID:28380382 A Single Adaptable Cochaperone-Scaffold Complex Delivers Nas... | KEEP AS NON CORE | Summary: Bare 'protein binding' representing the HSPA9-HSC20/HSCB (Q8IWL3) co-chaperone-scaffold interaction that delivers nascent Fe-S clusters to respiratory chain Complexes I-III. Mechanistically core to Fe-S biogenesis, but the GO term itself is uninformative. Reason: Genuine and mechanistically important interaction in Fe-S delivery (functionally captured by GO:0016226), but 'protein binding' is uninformative as a standalone MF. Retain as non-core. Supporting Evidence: PMID:28380382 A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a large-scale human interactome map (interactors Q9H6A0, Q9HAV7). High-throughput, uninformative MF term. Reason: GO:0005515 is uninformative and this is a non-specific interactome/affinity-MS hit. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a crosslinking-MS histone-interaction study in intact nuclei (interactor Q9HAV7). High-throughput, uninformative MF term suggesting only a transient nuclear-associated pool. Reason: GO:0005515 is uninformative and this XL-MS co-occurrence does not define a specific HSPA9 function; a nuclear pool is at best minor and non-core. Supporting Evidence: PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. |
| GO:0005515 protein binding | IPI PMID:31978385 TGR5 promotes cholangiocarcinoma by interacting with mortali... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor TGR5/GPBAR1, Q8TDU6) from a cholangiocarcinoma study. A disease-context interaction but the MF term is uninformative. Reason: GO:0005515 is uninformative; this cancer-context interaction does not define a core or specific HSPA9 molecular function. Supporting Evidence: PMID:31978385 TGR5 promotes cholangiocarcinoma by interacting with mortalin. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor EGFR/P00533) from an EGFR-network rewiring study in KRAS-mutant colorectal cancer cells. High-throughput, uninformative MF term. Reason: GO:0005515 is uninformative and this is a non-specific interactome hit, not a defined HSPA9 function. Supporting Evidence: PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D). |
| GO:0005515 protein binding | IPI PMID:32807793 OSMR controls glioma stem cell respiration and confers resis... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor OSMR/Q99650) from a glioblastoma respiration/radioresistance study. High-throughput proteomics association, uninformative MF term. Reason: GO:0005515 is uninformative; this cancer-context proteomics co-occurrence does not define a specific HSPA9 function. Supporting Evidence: PMID:32807793 OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from dual proteome-scale interactome networks (interactors Q9H6A0, Q9HAV7). High-throughput, uninformative MF term. Reason: GO:0005515 is uninformative and this is a non-specific large-scale interactome hit. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0016226 iron-sulfur cluster assembly | IEA GO_REF:0000107 | ACCEPT | Summary: Iron-sulfur cluster assembly transferred by Ensembl Compara orthology from mouse Hspa9. Duplicate of the IBA and IMP Fe-S assembly calls, all consistent with direct human experimental evidence. Reason: Correct core process; redundant with stronger IBA/IMP evidence (PMID:26702583, PMID:23940031) but accurate. Supporting Evidence: PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0019899 enzyme binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Enzyme binding transferred by Ensembl Compara orthology. HSPA9 does bind enzymes (e.g., cysteine desulfurase NFS1 in Fe-S biogenesis), but 'enzyme binding' is a relatively uninformative molecular function term derived from orthology transfer. Reason: While HSPA9 contacts enzymes such as NFS1, the generic 'enzyme binding' term adds little functional specificity beyond the better-supported chaperone and Fe-S assembly annotations; it is an orthology-transferred over-annotation. Supporting Evidence: PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU). |
| GO:1902037 negative regulation of hematopoietic stem cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of hematopoietic stem cell differentiation transferred by Ensembl Compara orthology from mouse Hspa9, where knockdown perturbs hematopoietic progenitors. This is a downstream physiological consequence of HSPA9's Fe-S/chaperone function rather than a direct molecular role. Reason: Supported indirectly by mouse loss-of-function data (PMID:21123823), but this is a pleiotropic developmental/physiological outcome secondary to HSPA9's core mitochondrial chaperone and Fe-S biogenesis functions. Keep as non-core. Supporting Evidence: PMID:21123823 Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. |
| GO:1903707 negative regulation of hemopoiesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of hemopoiesis transferred by Ensembl Compara orthology from mouse Hspa9. A broad pleiotropic/physiological outcome of HSPA9's mitochondrial function rather than a direct molecular role. Reason: Indirectly supported by mouse loss-of-function studies (PMID:21123823), but it is a downstream consequence of impaired Fe-S/chaperone function and not a core HSPA9 activity. Keep as non-core. Supporting Evidence: PMID:21123823 Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Mitochondrion localization from curated immunofluorescence (Human Protein Atlas). Directly confirms the canonical mitochondrial localization of HSPA9. Reason: Direct experimental localization consistent with all other evidence for HSPA9 as a mitochondrial protein. Supporting Evidence: PMID:7829505 Cloning and subcellular localization of human mitochondrial hsp70. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:10339406 Genetic and structural characterization of the human mitocho... | ACCEPT | Summary: Mitochondrial inner membrane localization (ComplexPortal NAS). HSPA9 is the matrix-side motor of the TIM23/PAM import machinery and is recruited to the inner membrane translocase during import, so an inner-membrane-associated pool is mechanistically expected. Reason: HSPA9 functions at the inner membrane as the PAM motor associated with the TIM23 translocase; the inner-membrane association is well-established for mtHsp70 import function. Supporting Evidence: PMID:10339406 Genetic and structural characterization of the human mitochondrial inner membrane translocase. |
| GO:0006886 intracellular protein transport | NAS PMID:10339406 Genetic and structural characterization of the human mitocho... | MODIFY | Summary: Intracellular protein transport (ComplexPortal NAS) referring to HSPA9's role as the PAM motor of the TIM23 import machinery. The specific process is import of nuclear-encoded precursors into the mitochondrial matrix; the generic term is too broad. Reason: HSPA9 drives a specific transport process - ATP-dependent import of presequence-containing precursors across the inner membrane into the matrix. GO:0030150 (protein import into mitochondrial matrix) is the appropriately specific term and is used in core_functions. Proposed replacements: protein import into mitochondrial matrix Supporting Evidence: PMID:10339406 Genetic and structural characterization of the human mitochondrial inner membrane translocase. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:18632665 The human escort protein Hep binds to the ATPase domain of m... | ACCEPT | Summary: ATP hydrolysis activity demonstrated by direct biochemical assay; the escort protein Hep/DNLZ binds the HSPA9 ATPase domain and regulates its ATP hydrolysis. Direct experimental support for the core catalytic activity. Reason: Strong direct (IDA) evidence for HSPA9 ATPase activity, the core catalytic function powering its chaperone cycle. Supporting Evidence: PMID:18632665 The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:25615450 Human mitochondrial Hsp70 (mortalin): shedding light on ATPa... | ACCEPT | Summary: ATP hydrolysis activity directly characterized for human mortalin, including ATPase kinetics, nucleotide interactions, solution structure and Hsp70 two-domain organization. Direct experimental support for the core catalytic activity. Reason: Direct (IDA) biochemical characterization of human HSPA9 ATPase activity; this is the core molecular function. Supporting Evidence: PMID:25615450 Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Mitochondrion localization from a high-confidence quantitative human mitochondrial proteome. Corroborates the canonical mitochondrial localization of HSPA9. Reason: HSPA9 is a bona fide, high-confidence component of the human mitochondrial proteome; consistent with all other localization evidence. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0036444 calcium import into the mitochondrion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Calcium import into the mitochondrion by ISS from ortholog (UniProtKB:P48721, GRP75). GRP75/mortalin is a scaffolding component of the IP3R-GRP75-VDAC1 complex at mitochondria-associated ER membranes (MAMs) that channels ER-to-mitochondria Ca2+ transfer. This is a genuine but secondary, scaffolding role rather than HSPA9's core matrix chaperone function. Reason: GRP75/HSPA9 bridges IP3R and VDAC1 at MAMs to facilitate Ca2+ transfer, but this is a context-dependent scaffolding role at the mitochondrial surface, distinct from and secondary to its core matrix chaperone/import/Fe-S functions. Retain as non-core. Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md Mortalin can redistribute beyond mitochondria (including plasma membrane accumulation) under certain stresses |
| GO:0005759 mitochondrial matrix | IDA PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock prote... | ACCEPT | Summary: Mitochondrial matrix localization by direct assay (PBP74/HSPA9 shown to be a mitochondrial protein). This is the primary, functionally relevant compartment for HSPA9. Reason: Direct experimental localization to the matrix, the core site of HSPA9 chaperone, import-motor, and Fe-S delivery functions. Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0005515 protein binding | IPI PMID:24625977 Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, prom... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactors p53/P04637 and UBXN2A/P68543). UBXN2A binds mortalin and competes with p53 for mortalin binding, promoting cell death. Mechanistically relevant to mortalin's p53-sequestration role but the MF term is uninformative. Reason: GO:0005515 is uninformative; the p53/UBXN2A interactions relate to mortalin's cancer-context anti-apoptotic role and are not a core or specifically-defined molecular function. UBXN2A binding is also captured separately (PMID:26634371). Supporting Evidence: PMID:24625977 Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells. |
| GO:0005515 protein binding | IPI PMID:26634371 Structural studies of UBXN2A and mortalin interaction and th... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor UBXN2A/P68543) from structural studies of the UBXN2A-mortalin interaction. A direct, structurally characterized interaction relevant to chemotherapy response, but the MF term is uninformative. Reason: GO:0005515 is uninformative; the UBXN2A interaction relates to mortalin's cancer/p53 biology and is not a core HSPA9 molecular function. Supporting Evidence: PMID:26634371 Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy. |
| GO:0005515 protein binding | IPI PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfu... | KEEP AS NON CORE | Summary: Bare 'protein binding' representing the direct HSPA9 (mtHSP70)-ISCU (Q9H1K1) interaction, where mtHSP70 binds preferentially to the disordered conformation of the Fe-S scaffold ISCU. This is a mechanistically core interaction in Fe-S cluster delivery, but the GO term is uninformative. Reason: The HSPA9-ISCU interaction is central to Fe-S cluster biogenesis (functionally captured by GO:0016226 and the GO:0044183 core function), but 'protein binding' is uninformative as a standalone MF. Retain as non-core documentation of the substrate/scaffold interaction. Supporting Evidence: PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU). |
| GO:0001401 SAM complex | HDA PMID:26477565 Evolution and structural organization of the mitochondrial c... | MARK AS OVER ANNOTATED | Summary: SAM complex membership from a high-throughput proteomics analysis of MICOS/MIB assemblies. The SAM complex is an outer-membrane sorting-and-assembly machinery; HSPA9 is a soluble matrix chaperone and not an established structural subunit of SAM, so this is most likely a co-purification artifact or transient association. Reason: HSPA9 is a matrix Hsp70, not a bona fide structural component of the outer-membrane SAM complex; the HDA assignment reflects co-fractionation with large mitochondrial assemblies rather than stable SAM membership. Supporting Evidence: PMID:26477565 Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. |
| GO:0007007 inner mitochondrial membrane organization | IC PMID:26477565 Evolution and structural organization of the mitochondrial c... | MARK AS OVER ANNOTATED | Summary: Inner mitochondrial membrane organization inferred (IC) from the putative MIB-complex membership. Since the underlying MIB/SAM association is most likely a co-fractionation artifact for this matrix chaperone, the inferred membrane-organization process is not well supported. Reason: This IC annotation depends on HSPA9 being a structural component of the MIB complex, which is not established for a matrix Hsp70; the inner-membrane-organization role is therefore an over-annotation. Supporting Evidence: PMID:26477565 Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. |
| GO:0140275 MIB complex | HDA PMID:26477565 Evolution and structural organization of the mitochondrial c... | MARK AS OVER ANNOTATED | Summary: MIB complex membership from high-throughput proteomics of MICOS/MIB assemblies. The MIB complex bridges inner and outer membranes; HSPA9 is a matrix chaperone and not an established structural subunit, so this most likely reflects co-purification rather than stable membership. Reason: HSPA9 is not a bona fide structural component of the MIB complex; the HDA assignment reflects co-fractionation with large mitochondrial assemblies. Supporting Evidence: PMID:26477565 Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. |
| GO:0016226 iron-sulfur cluster assembly | IMP PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentia... | ACCEPT | Summary: Iron-sulfur cluster assembly supported by mutational evidence (IMP). HSPA9/mortalin regulates Fe-S cluster assembly; a Gly489 mutation disrupts ISC assembly function and HSPA9 binds Fe-S pathway components (ISCU, NFS1, NFU1, FXN). Strong direct evidence for this core process. Reason: Direct mutational/functional evidence places HSPA9 in Fe-S cluster assembly, a core biological process; this IMP is the strongest support and complements the IBA/IEA calls. Supporting Evidence: PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0005515 protein binding | IPI PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentia... | KEEP AS NON CORE | Summary: Bare 'protein binding' representing HSPA9 interactions with Fe-S pathway components ISCU (Q9H1K1), FXN/frataxin (Q16595), NFU1 (Q9UMS0) and NFS1 (Q9Y697). These are mechanistically core Fe-S biogenesis interactions, but the GO term itself is uninformative. Reason: The interactions with ISCU/FXN/NFU1/NFS1 underpin HSPA9's Fe-S cluster assembly function (captured by GO:0016226), but 'protein binding' is uninformative as a standalone MF. Retain as non-core documentation of the Fe-S partner interactions. Supporting Evidence: PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0005739 mitochondrion | IDA PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentia... | ACCEPT | Summary: Mitochondrion localization by direct assay, corroborating the canonical mitochondrial localization of HSPA9/mortalin. Reason: Direct experimental localization consistent with all other evidence; HSPA9 is a mitochondrial protein. Supporting Evidence: PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0045646 regulation of erythrocyte differentiation | IMP PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentia... | KEEP AS NON CORE | Summary: Regulation of erythrocyte differentiation by mutational evidence (IMP). HSPA9 loss impairs erythroid differentiation, mechanistically via its Fe-S cluster assembly role. This is a downstream physiological consequence of the core mitochondrial function. Reason: Genuine, experimentally supported role in erythroid differentiation, but it is a tissue-level developmental outcome secondary to HSPA9's core Fe-S/chaperone function. Keep as non-core. Supporting Evidence: PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0005515 protein binding | IPI PMID:23541579 Extracellular heat shock protein A9 is a novel interaction p... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' (interactor podoplanin/Q86YL7) describing an extracellular mortalin-podoplanin interaction in oral squamous cell carcinoma. A context-dependent extracellular interaction; the MF term is uninformative. Reason: GO:0005515 is uninformative; this extracellular cancer-context interaction does not define a core HSPA9 molecular function. Supporting Evidence: PMID:23541579 Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-8950389 | ACCEPT | Summary: Mitochondrial matrix localization asserted by Reactome (expression of mitochondrial Stress-70 protein). Consistent with the primary matrix localization of HSPA9. Reason: Correct localization to the matrix, the core compartment of HSPA9 function; consistent with direct experimental evidence (PMID:7865888). Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: Mitochondrial matrix localization asserted by Reactome (CLPXP binds mitochondrial matrix proteins event). Consistent with HSPA9's primary matrix localization where it cooperates with matrix proteostasis machinery. Reason: Correct matrix localization; consistent with direct experimental evidence and HSPA9's role in matrix protein quality control. Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838081 | ACCEPT | Summary: Mitochondrial matrix localization asserted by Reactome (LONP1 degrades mitochondrial matrix proteins event). Consistent with HSPA9's primary matrix localization within the matrix proteostasis network. Reason: Correct matrix localization; consistent with direct experimental evidence. Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838093 | ACCEPT | Summary: Mitochondrial matrix localization asserted by Reactome (LONP1 binds mitochondrial matrix proteins event). Consistent with HSPA9's primary matrix localization. Reason: Correct matrix localization; consistent with direct experimental evidence. Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Mitochondrial matrix localization asserted by Reactome (CLPXP degrades mitochondrial matrix proteins event). Consistent with HSPA9's primary matrix localization. Reason: Correct matrix localization; consistent with direct experimental evidence. Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9856627 | ACCEPT | Summary: Mitochondrial matrix localization asserted by Reactome (ATF5 and HSF1 trimer activate expression of HSPA9/mtHSP70 event). Consistent with HSPA9's primary matrix localization and stress-responsive upregulation. Reason: Correct matrix localization; consistent with direct experimental evidence. Supporting Evidence: PMID:7865888 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. |
| GO:0030218 erythrocyte differentiation | IMP PMID:21123823 Knockdown of Hspa9, a del(5q31.2) gene, results in a decreas... | KEEP AS NON CORE | Summary: Erythrocyte differentiation by mutational/knockdown evidence (IMP). Hspa9 knockdown reduces hematopoietic progenitors in mice, implicating HSPA9 in erythroid development. This is a downstream physiological consequence of its core mitochondrial function. Reason: Experimentally supported developmental involvement, but a tissue-level outcome secondary to HSPA9's core Fe-S/chaperone function. Keep as non-core. Supporting Evidence: PMID:21123823 Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. |
| GO:0045647 negative regulation of erythrocyte differentiation | IMP PMID:21123823 Knockdown of Hspa9, a del(5q31.2) gene, results in a decreas... | KEEP AS NON CORE | Summary: Negative regulation of erythrocyte differentiation (IMP). Note that loss of Hspa9 reduces hematopoietic progenitors, so HSPA9 normally supports rather than negatively regulates erythropoiesis; the directionality of this term is questionable and likely reflects a complex dosage phenotype at the del(5q) locus. Reason: HSPA9 is involved in erythroid differentiation, but it is a downstream developmental phenotype and the negative-regulation directionality is not cleanly supported (knockdown decreases progenitors). Retain as non-core given the experimental link, without elevating it to a core function. Supporting Evidence: PMID:21123823 Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19725078 Proteomic analysis of increased Parkin expression and its in... | KEEP AS NON CORE | Summary: Ubiquitin protein ligase binding (interactor Parkin/PRKN, O60260) from proteomic analysis of Parkin interactants. HSPA9/mortalin associates with the E3 ligase Parkin in the context of mitochondrial quality control/mitophagy. More informative than bare protein binding but a peripheral interaction. Reason: The HSPA9-Parkin association is genuine and relevant to mitochondrial quality control, but it is peripheral to HSPA9's core chaperone/import/Fe-S functions. Keep as non-core. Supporting Evidence: PMID:19725078 Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. | KEEP AS NON CORE | Summary: Ubiquitin protein ligase binding (interactor Parkin/PRKN, O60260) reported in a Parkin/Ambra1 mitophagy study. Corroborates the HSPA9-Parkin association in mitochondrial quality control. Peripheral interaction. Reason: Genuine HSPA9-Parkin association relevant to mitophagy/quality control, but peripheral to HSPA9's core functions. Keep as non-core. Supporting Evidence: PMID:21753002 Parkin interacts with Ambra1 to induce mitophagy. |
| GO:0005925 focal adhesion | HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome... | MARK AS OVER ANNOTATED | Summary: Focal adhesion localization from a high-throughput focal-adhesion proteome. HSPA9 is a mitochondrial matrix protein; its appearance in a focal-adhesion fraction is most likely a contaminant/co-isolation artifact rather than a genuine functional localization. Reason: Inconsistent with HSPA9's established mitochondrial matrix localization; HDA detection in a focal-adhesion proteome likely reflects abundant-protein contamination and is not a functional site. Supporting Evidence: PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for beta-Pix in negative regulation of focal adhesion maturation. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: RNA binding from a high-throughput mRNA-interactome capture (RNA-protein crosslinking) atlas. HSPA9 lacks a canonical RNA-binding domain; Hsp70 chaperones are frequently captured in such screens, so this likely reflects chaperone association with RNP/nascent-chain complexes rather than direct sequence-specific RNA binding. Reason: No canonical RNA-binding domain and no dedicated functional evidence for sequence-specific RNA binding; the HDA call is a non-specific interactome-capture hit and over-annotates HSPA9's molecular function. Supporting Evidence: PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | MARK AS OVER ANNOTATED | Summary: RNA binding from a high-throughput mRNA-bound proteome capture. As above, HSPA9 has no canonical RNA-binding domain and such captures of Hsp70s likely reflect chaperone association with RNP complexes rather than direct RNA binding. Reason: Non-specific interactome-capture hit lacking functional or domain support for sequence-specific RNA binding; over-annotates HSPA9's molecular function. Supporting Evidence: PMID:22681889 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Extracellular exosome localization from a high-throughput exosome proteome (B-cell exosomes). Extracellular/exosomal pools of mortalin are reported, consistent with regulated extramitochondrial redistribution, but this is a minor, context-dependent localization rather than the core matrix site. Reason: Exosomal/extracellular mortalin is documented and biologically relevant in some contexts (e.g., cancer signaling), but it is non-core relative to HSPA9's mitochondrial matrix function. Keep as non-core. Supporting Evidence: file:human/HSPA9/HSPA9-deep-research-falcon.md mortalin also participates in extracellular processes including modulation of complement-mediated cytotoxicity, illustrating context-dependent trafficking beyond the matrix |
| GO:0005515 protein binding | IPI PMID:20668094 Characterization of the human HSC20, an unusual DnaJ type II... | KEEP AS NON CORE | Summary: Bare 'protein binding' representing the HSPA9-HSC20/HSCB (Q8IWL3) co-chaperone interaction; HSC20 is the DnaJ type III J-protein that partners with mtHsp70 in Fe-S cluster biogenesis. Mechanistically core to Fe-S delivery, but the MF term is uninformative. Reason: The HSPA9-HSC20 J-protein partnership is central to Fe-S cluster biogenesis (captured functionally by GO:0016226), but 'protein binding' is uninformative as a standalone MF. Retain as non-core. Supporting Evidence: PMID:20668094 Characterization of the human HSC20, an unusual DnaJ type III protein, involved in iron-sulfur cluster biogenesis. |
| GO:0005515 protein binding | IPI PMID:15520177 Tid1, the human homologue of a Drosophila tumor suppressor, ... | KEEP AS NON CORE | Summary: Bare 'protein binding' representing the HSPA9-TID1/DNAJA3 (Q96EY1) interaction. TID1 is a mitochondrial J-domain (DnaJ) co-chaperone that regulates mtHsp70 activity. Functionally meaningful co-chaperone interaction, but the MF term is uninformative. Reason: The HSPA9-DNAJA3/TID1 J-protein interaction is mechanistically relevant to the Hsp70 chaperone cycle, but 'protein binding' is uninformative as a standalone MF. Retain as non-core. Supporting Evidence: PMID:15520177 Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells. |
| GO:0005515 protein binding | IPI PMID:10411904 TID1, a human homolog of the Drosophila tumor suppressor l(2... | KEEP AS NON CORE | Summary: Bare 'protein binding' representing the HSPA9-TID1/DNAJA3 (Q96EY1) interaction; TID1 isoforms are mitochondrial J-domain co-chaperones that modulate apoptosis with opposing functions. Functionally meaningful co-chaperone interaction, but the MF term is uninformative. Reason: The HSPA9-DNAJA3/TID1 J-protein interaction is relevant to the mtHsp70 chaperone cycle, but 'protein binding' is uninformative as a standalone MF. Retain as non-core. Supporting Evidence: PMID:10411904 TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions. |
| GO:0005739 mitochondrion | IDA PMID:7896880 The intracellular distribution and pattern of expression of ... | ACCEPT | Summary: Mitochondrion localization by direct assay, corroborating the canonical mitochondrial localization of HSPA9. Reason: Direct experimental localization consistent with all other evidence; HSPA9 is a mitochondrial protein. Supporting Evidence: PMID:7896880 The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2. |
| GO:0042645 mitochondrial nucleoid | IDA PMID:18063578 The layered structure of human mitochondrial DNA nucleoids. | KEEP AS NON CORE | Summary: Mitochondrial nucleoid localization by direct assay. HSPA9/mortalin was identified among proteins of the layered mtDNA nucleoid, consistent with a peripheral nucleoid-associated matrix pool. mtHsp70 has documented associations with mtDNA maintenance. Reason: A specific matrix sub-localization supported by direct evidence; nucleoid association is genuine but secondary to HSPA9's core chaperone/import/Fe-S roles. Keep as non-core. Supporting Evidence: PMID:18063578 The layered structure of human mitochondrial DNA nucleoids. |
| GO:0005739 mitochondrion | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | ACCEPT | Summary: Mitochondrion localization (TAS) from a HUVEC apoptosis proteomics study. Consistent with the canonical mitochondrial localization of HSPA9. Reason: Correct localization consistent with all other evidence. Supporting Evidence: PMID:16130169 Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis. |
| GO:0043066 negative regulation of apoptotic process | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process (TAS). HSPA9/mortalin has a documented anti-apoptotic role, notably through cytosolic sequestration of p53 and stabilization of mitochondrial integrity. This is a genuine but context-dependent function relevant to its cancer biology. Reason: The anti-apoptotic activity (largely via p53 sequestration) is well supported and biologically important, but it is a context-dependent regulatory role distinct from HSPA9's core matrix chaperone/import/Fe-S functions. Keep as non-core. Supporting Evidence: PMID:20153329 Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins--identification of additional interacting regions. |
| GO:0051082 unfolded protein binding | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | MODIFY | Summary: The TAS source does not provide a mechanistic assay of direct unfolded-protein binding by HSPA9. For HSPA9, the informative MF is ATP-dependent Hsp70 chaperone activity in mitochondrial protein import/folding rather than generic unfolded-protein binding. Reason: HSPA9 is a mitochondrial Hsp70 foldase chaperone (mtHsp70/mortalin). GO:0051082 is too generic and does not reflect the ATP-driven chaperone cycle; GO:0044183 better captures the molecular mechanism. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:16130169 Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis. file:human/HSPA9/HSPA9-deep-research-falcon.md HSPA9 performs ATP-driven pulling/unfolding action that drives translocation of presequence-containing proteins and functions as the core of the presequence translocase-associated motor (PAM). |
| GO:0005737 cytoplasm | TAS PMID:7684501 Cloning of the gene encoding peptide-binding protein 74 show... | KEEP AS NON CORE | Summary: Cytoplasm localization (TAS) from an early cloning study of PBP74/HSPA9, which reported cytoplasmic localization before mitochondrial targeting was fully established. A transient cytosolic precursor pool and stress-induced extramitochondrial pools exist, but the dominant functional site is the mitochondrial matrix. Reason: Reflects an early/partial localization assignment; the functionally relevant compartment is the mitochondrial matrix. Cytoplasmic pool is the transient precursor plus minor extramitochondrial redistribution. Keep as non-core. Supporting Evidence: PMID:7684501 Cloning of the gene encoding peptide-binding protein 74 shows that it is a new member of the heat shock protein 70 family. |
| GO:0005739 mitochondrion | TAS PMID:7829505 Cloning and subcellular localization of human mitochondrial ... | ACCEPT | Summary: Mitochondrion localization (TAS) from the cloning and subcellular-localization study of human mitochondrial Hsp70 (HSPA9), establishing its mitochondrial localization. Reason: Foundational localization evidence consistent with all subsequent data; HSPA9 is a canonical mitochondrial protein. Supporting Evidence: PMID:7829505 Cloning and subcellular localization of human mitochondrial hsp70. |
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Download this section (compressed HTML)Q: What is the structural basis for the substrate handoff between HSPA9 (mtHsp70) and HSC20/HSCB-ISCU during iron-sulfur cluster transfer to client apoproteins?
Q: Under which physiological conditions and via which trafficking routes does mortalin redistribute to the plasma membrane, cytosol, exosomes or extracellular space, and is this dependent on the mitochondrial targeting sequence cleavage?
Q: Do EVEN-PLUS and SIDBA4 disease-associated HSPA9 variants impair PAM-mediated import, ISC delivery, or general chaperone activity, and which co-chaperone pathway is most sensitive to ATPase domain mutations?
Experiment: Reconstitute the human PAM import motor with purified HSPA9, GRPEL1/2, Pam16/Magmas, Pam18/DNAJC15/19 and a model presequence-containing client to measure ATP-hydrolysis kinetics and translocation efficiency in proteoliposomes, contrasting wild-type with disease-associated HSPA9 variants.
Experiment: Use proximity-labeling proteomics (BioID/TurboID) on HSPA9 in mitochondria versus stress-induced extracellular fractions to define context-dependent interactomes and verify whether mortalin maintains its chaperone partners (HSC20, ISCU, DNAJC15) outside the matrix.
Experiment: Quantify Fe-S cluster delivery to specific apoprotein clients (e.g., complex I subunits, aconitase) in HSPA9-knockdown cells reconstituted with separation-of-function HSPA9 mutants impairing HSC20 binding versus ATPase activity.
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