Existing Annotations Review

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10339406

Genetic and structural characterization of the human mitochondrial inner membrane translocase.

PMID:10411904

TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions.

PMID:15520177

Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells.

PMID:15657067

Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells.

PMID:16130169

Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.

PMID:17184779

Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis.

PMID:18063578

The layered structure of human mitochondrial DNA nucleoids.

PMID:18632665

The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.

PMID:19725078

Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function.

PMID:20029029

Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.

PMID:20153329

Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins--identification of additional interacting regions.

PMID:20195357

A comprehensive resource of interacting protein regions for refining human transcription factor networks.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:20668094

Characterization of the human HSC20, an unusual DnaJ type III protein, involved in iron-sulfur cluster biogenesis.

PMID:21123823

Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice.

PMID:21423176

Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.

PMID:21753002

Parkin interacts with Ambra1 to induce mitophagy.

PMID:22340593

Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

PMID:22726440

p53 opens the mitochondrial permeability transition pore to trigger necrosis.

PMID:23541579

Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells.

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).

PMID:24189400

Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.

PMID:24606901

Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery.

PMID:24625977

Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25615450

Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization.

PMID:26477565

Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex.

PMID:26634371

Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy.

PMID:26702583

Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.

PMID:27107014

An inter-species protein-protein interaction network across vast evolutionary distance.

PMID:27607350

Characterization of the Translationally Controlled Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells.

PMID:28380382

A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:30021884

Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.

PMID:31978385

TGR5 promotes cholangiocarcinoma by interacting with mortalin.

PMID:31980649

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).

PMID:32807793

OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

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.

PMID:7829505

Cloning and subcellular localization of human mitochondrial hsp70.

PMID:7865888

PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.

PMID:7896880

The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2.

Reactome:R-HSA-8950389

Expression of Stress-70 protein, mitochondrial

Reactome:R-HSA-9838035

CLPXP binds mitochondrial matrix proteins

Reactome:R-HSA-9838081

LONP1 degrades mitochondrial matrix proteins

Reactome:R-HSA-9838093

LONP1 binds mitochondrial matrix proteins

Reactome:R-HSA-9838289

CLPXP degrades mitochondrial matrix proteins

Reactome:R-HSA-9856627

ATF5 and HSF1 trimer activate expression of HSPA9 (mtHSP70)

file:human/HSPA9/HSPA9-deep-research-falcon.md

Deep research report on HSPA9

📚 Additional Documentation

Deep Research Falcon

(HSPA9-deep-research-falcon.md)

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organism: human
gene_id: HSPA9
gene_symbol: HSPA9
uniprot_accession: P38646
protein_description: 'RecName: Full=Stress-70 protein, mitochondrial {ECO:0000305};
EC=3.6.4.10 {ECO:0000269|PubMed:18632665, ECO:0000269|PubMed:25615450, ECO:0000269|PubMed:30933555,
ECO:0000269|PubMed:31177526}; AltName: Full=75 kDa glucose-regulated protein;
Short=GRP-75; AltName: Full=Heat shock 70 kDa protein 9; AltName: Full=Heat shock
protein family A member 9; AltName: Full=Mortalin; Short=MOT; AltName: Full=Peptide-binding
protein 74; Short=PBP74; Flags: Precursor;'
gene_info: Name=HSPA9 {ECO:0000312|HGNC:HGNC:5244}; Synonyms=GRP75, HSPA9B, mt-HSP70
{ECO:0000303|PubMed:18632665};
organism_full: Homo sapiens (Human).
protein_family: Belongs to the heat shock protein 70 family. .
protein_domains: ATPase_NBD. (IPR043129); Chaperone_DnaK. (IPR012725); Heat_shock_70_CS.
(IPR018181); HSP70_C_sf. (IPR029048); HSP70_peptide-bd_sf. (IPR029047)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P38646
Protein Description: RecName: Full=Stress-70 protein, mitochondrial {ECO:0000305}; EC=3.6.4.10 {ECO:0000269|PubMed:18632665, ECO:0000269|PubMed:25615450, ECO:0000269|PubMed:30933555, ECO:0000269|PubMed:31177526}; AltName: Full=75 kDa glucose-regulated protein; Short=GRP-75; AltName: Full=Heat shock 70 kDa protein 9; AltName: Full=Heat shock protein family A member 9; AltName: Full=Mortalin; Short=MOT; AltName: Full=Peptide-binding protein 74; Short=PBP74; Flags: Precursor;
Gene Information: Name=HSPA9 {ECO:0000312|HGNC:HGNC:5244}; Synonyms=GRP75, HSPA9B, mt-HSP70 {ECO:0000303|PubMed:18632665};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the heat shock protein 70 family. .
Key Domains: ATPase_NBD. (IPR043129); Chaperone_DnaK. (IPR012725); Heat_shock_70_CS. (IPR018181); HSP70_C_sf. (IPR029048); HSP70_peptide-bd_sf. (IPR029047)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "HSPA9" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'HSPA9' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene HSPA9 (gene ID: HSPA9, UniProt: P38646) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P38646
Protein Description: RecName: Full=Stress-70 protein, mitochondrial {ECO:0000305}; EC=3.6.4.10 {ECO:0000269|PubMed:18632665, ECO:0000269|PubMed:25615450, ECO:0000269|PubMed:30933555, ECO:0000269|PubMed:31177526}; AltName: Full=75 kDa glucose-regulated protein; Short=GRP-75; AltName: Full=Heat shock 70 kDa protein 9; AltName: Full=Heat shock protein family A member 9; AltName: Full=Mortalin; Short=MOT; AltName: Full=Peptide-binding protein 74; Short=PBP74; Flags: Precursor;
Gene Information: Name=HSPA9 {ECO:0000312|HGNC:HGNC:5244}; Synonyms=GRP75, HSPA9B, mt-HSP70 {ECO:0000303|PubMed:18632665};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the heat shock protein 70 family. .
Key Domains: ATPase_NBD. (IPR043129); Chaperone_DnaK. (IPR012725); Heat_shock_70_CS. (IPR018181); HSP70_C_sf. (IPR029048); HSP70_peptide-bd_sf. (IPR029047)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "HSPA9" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene HSPA9 (gene ID: HSPA9, UniProt: P38646) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification summary
- Verified identity: The target is human HSPA9 (aliases: GRP75, mortalin, mtHsp70, PBP74, HSP75), a mitochondrial Hsp70-family chaperone encoded in Homo sapiens. Reviews explicitly describe these aliases, a mitochondrial targeting sequence, and mitochondrial localization, with reported extra‑mitochondrial pools under specific conditions (e.g., stress/complement) (esfahanian2023mortalinproteinpartners pages 1-2, esfahanian2023mortalinproteinpartners pages 10-11).

Comprehensive research report

1) Key concepts and definitions with current understanding
- Identity and family: 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. A review details its aliases, mitochondrial targeting sequence, and role in mitochondrial protein quality control (esfahanian2023mortalinproteinpartners pages 1-2, esfahanian2023mortalinproteinpartners pages 9-10). Functionally, mortalin cooperates with mitochondrial J‑proteins and NEFs analogous to other Hsp70 systems (esfahanian2023mortalinproteinpartners pages 9-10). Mortalin can redistribute beyond mitochondria (including plasma membrane accumulation) under certain stresses such as complement attack, indicating regulated extra‑mitochondrial pools (esfahanian2023mortalinproteinpartners pages 10-11).
- Catalytic activity: As an Hsp70, HSPA9 is an ATP‑dependent chaperone (EC 3.6.4.10), cycling between ATP- and ADP-bound states to capture/release unfolded polypeptides; kinetic/structural characterizations of human mortalin support this chaperone mechanism (esfahanian2023mortalinproteinpartners pages 9-10).

2) Recent developments and latest research (2023–2024 priority)
- PAM import motor and mitochondrial protein import: A 2024 mini‑review on disease-causing mutations in the TIM23/PAM system emphasizes that mitochondrial Hsp70 (mortalin/HSPA9) is “the heart of the PAM complex,” providing the import motor function. It highlights regulation of mtHsp70 ATPase activity by PAM J‑protein regulators Tim14 (Pam18/DNAJC15/19) and Tim16 (Pam16/Magmas), and connects these components to human disease (Genes, Nov 2024; URL: https://doi.org/10.3390/genes15121534) (jain2024hotspotsfordiseasecausing pages 7-8).
- Iron–sulfur (Fe–S) cluster biogenesis: A 2024 review focusing on viral Fe–S proteins summarizes the mammalian ISC pathway, explicitly stating that HSPA9 (mitochondrial Hsp70) with its J‑domain cochaperone HSC20/HSCB facilitates transfer of Fe–S clusters from the ISCU scaffold to recipient proteins; HSC20 recognizes LYR‑motif clients and directly interacts with ISCU (Inorganics, Jan 2024; URL: https://doi.org/10.20944/preprints202312.1414.v1) (heffner2024tipofthe pages 2-4).
- Translational pharmacology updates around Hsp70/mortalin inhibition: Reviews spanning 2023–2024 catalog mortalin‑targeting strategies and preclinical agents, noting the historical mitochondrial-targeted Hsp70 inhibitor MKT‑077 (Phase I in the 1990s) and newer analogs, while underscoring remaining gaps in specificity and toxicity (Cancers, Oct 2024; URL: https://doi.org/10.3390/cancers16203470) (kaushal2024syntheticandnatural pages 16-17, hong2022analogsofthe pages 13-13).

3) Current applications and real‑world implementations
- Clinical translation of Hsp70/mortalin inhibitors: The cationic rhodacyanine MKT‑077, which accumulates in mitochondria and binds Hsp70 family proteins, reached a Phase I trial in chemo‑resistant solid tumors (Annals of Oncology, 1999; cited within Hong et al. 2022, Int J Mol Sci; URL: https://doi.org/10.3390/ijms23031063). Medicinal chemistry efforts produced next‑generation analogs (e.g., JG‑98/JG‑231) with preclinical efficacy in tumor models (Int J Mol Sci, 2022; URL above) (hong2022analogsofthe pages 13-13). Contemporary reviews summarize broader mortalin‑targeting agents (natural and synthetic) and emphasize the need for improved selectivity and delivery before widespread clinical use (Cancers, 2024; URL: https://doi.org/10.3390/cancers16203470) (kaushal2024syntheticandnatural pages 16-17).
- Functional cancer applications: Reviews synthesize evidence that mortalin is upregulated in several cancers and linked to EMT, stemness, and poor prognosis in certain contexts, supporting its use as a biomarker and a therapeutic target in oncology pipelines (Front. Cell Dev. Biol., Feb 2023; URL: https://doi.org/10.3389/fcell.2023.1028519) (esfahanian2023mortalinproteinpartners pages 10-10, esfahanian2023mortalinproteinpartners pages 9-10, esfahanian2023mortalinproteinpartners pages 1-2).

4) Expert opinions and analysis from authoritative sources
- Expert perspective on PAM and disease: The Genes (2024) analysis frames mtHsp70 as central to the mitochondrial presequence import motor and catalogs disease mutations across PAM/TIM23, highlighting how perturbations of mHsp70 regulation by DNAJC family co‑chaperones contribute to pathology—an expert synthesis aligning mechanistic biochemistry with human genetics (jain2024hotspotsfordiseasecausing pages 7-8).
- Expert synthesis on Fe–S assembly: The Inorganics (2024) review by Fe–S specialists details the mammalian ISC machinery and specifically assigns HSPA9/HSCB the role of cluster delivery from ISCU to clients, offering authoritative mechanistic context applicable to human physiology and disease (heffner2024tipofthe pages 2-4).
- Broad chaperone/mortalin role in disease: Recent reviews collate multi‑organism and multi‑system data linking mortalin to cancer biology, neurodegeneration, stress responses, and extracellular vesicle biology, underscoring its pleiotropic yet mechanistically grounded roles (Front. Cell Dev. Biol., 2023; Cancers, 2024) (esfahanian2023mortalinproteinpartners pages 10-10, esfahanian2023mortalinproteinpartners pages 10-11, kaushal2024syntheticandnatural pages 16-17).

5) Relevant statistics and data from recent studies
- Genetic disease links and phenotypes: The PAM/TIM23-focused report synthesizes multiple patient cohorts with HSPA9 mutations. It notes distinct pathogenic variants in HSPA9 linked to congenital sideroblastic anemia and EVEN‑PLUS syndrome, including truncating insertion and in‑frame deletions that lower mRNA/protein levels and target the ATPase domain (residues 1–360), with clinical findings such as anemia, iron overload, and developmental malformations (Genes, 2024; URL: https://doi.org/10.3390/genes15121534) (jain2024hotspotsfordiseasecausing pages 12-13, jain2024hotspotsfordiseasecausing pages 7-8). While the article is a mini‑review that compiles case-level statistics, it provides concrete mutation examples and associated phenotypes that illustrate disease burden.
- Cancer pharmacology data: The 2022 preclinical study reports that JG‑series analogs of MKT‑077 suppress medullary thyroid carcinoma cells in vitro and in xenografts; these data illustrate measurable anti‑tumor effects and support mechanism‑guided inhibitor optimization (Int J Mol Sci., 2022; URL: https://doi.org/10.3390/ijms23031063) (hong2022analogsofthe pages 13-13).

Biological mechanism and pathway integration
- Mitochondrial protein import via PAM: HSPA9 (mtHsp70/mortalin) performs the ATP‑driven pulling/unfolding action that drives translocation of presequence‑containing proteins across the inner membrane, functioning as the core of the presequence translocase‑associated motor (PAM). Its ATPase cycle is regulated by J‑domain proteins Tim14 (Pam18/DNAJC15/19) together with Tim16 (Pam16/Magmas), aligning mtHsp70 activity with import demands (Genes, 2024) (jain2024hotspotsfordiseasecausing pages 7-8).
- Fe–S cluster biogenesis (ISC pathway): Within the mitochondrial ISC system, nascent clusters assembled on ISCU are delivered to client apoproteins by a dedicated chaperone/co‑chaperone pair—HSPA9 with HSCB/HSC20—where HSCB binds LYR‑motif clients and ISCU and, together with HSPA9, transfers clusters in an ATP‑dependent manner. This function mechanistically places HSPA9 at a critical intersection of mitochondrial metabolism and genome maintenance pathways (Inorganics, 2024) (heffner2024tipofthe pages 2-4).

Subcellular localization
- Primary localization: HSPA9 predominantly resides in the mitochondrial matrix where it supports protein import and proteostasis; reviews describe an N‑terminal targeting sequence and extensive mitochondrial roles (esfahanian2023mortalinproteinpartners pages 1-2).
- Extra‑mitochondrial redistribution: Under complement attack, mortalin can relocalize from mitochondria to the plasma membrane; mortalin also participates in extracellular processes including modulation of complement‑mediated cytotoxicity, illustrating context‑dependent trafficking beyond the matrix (esfahanian2023mortalinproteinpartners pages 10-11).

Disease associations and mechanisms
- Inherited disease: HSPA9 pathogenic variants cause congenital sideroblastic anemia and EVEN‑PLUS syndrome; mechanistically, these mutations impair the ATPase domain or reduce protein abundance, consistent with loss of mitochondrial chaperone function (Genes, 2024) (jain2024hotspotsfordiseasecausing pages 12-13, jain2024hotspotsfordiseasecausing pages 7-8).
- Cancer: Mortalin overexpression is associated with pro‑tumor phenotypes (EMT, stemness, resistance), and is proposed as a prognostic biomarker in multiple cancers. Mechanistically, mitochondrial chaperone functions and extra‑mitochondrial interactions (e.g., p53 binding and complement interactions) contribute to oncogenic programs (Front. Cell Dev. Biol., 2023) (esfahanian2023mortalinproteinpartners pages 10-10, esfahanian2023mortalinproteinpartners pages 9-10, esfahanian2023mortalinproteinpartners pages 10-11).

Translational landscape: inhibitors, trials, and implementations
- Historical clinical experience: MKT‑077, a mitochondria‑accumulating Hsp70‑family ligand, advanced to Phase I in solid tumors, establishing feasibility but revealing safety limitations (cited within Hong et al., 2022; Int J Mol Sci.; URL: https://doi.org/10.3390/ijms23031063) (hong2022analogsofthe pages 13-13).
- Next‑generation Hsp70/mortalin modulators: JG‑series MKT‑077 analogs show preclinical potency in thyroid cancer models, and contemporary reviews catalog additional natural/synthetic mortalin inhibitors under investigation, while emphasizing unresolved issues of specificity, off‑target toxicity, and delivery (Int J Mol Sci., 2022; Cancers, 2024; URLs above) (hong2022analogsofthe pages 13-13, kaushal2024syntheticandnatural pages 16-17).

Notes on gene/protein identification and domain/family alignment
- The literature consistently refers to mortalin as the mitochondrial Hsp70 encoded by HSPA9, with aliases GRP75, mtHsp70, and PBP74 consistent with the UniProt entry provided. Its classification in the Hsp70 family and role as an ATP‑dependent chaperone strongly aligns with the ATPase NBD and peptide‑binding domain architecture typical for Hsp70s (esfahanian2023mortalinproteinpartners pages 1-2, esfahanian2023mortalinproteinpartners pages 9-10).

References with URLs and dates (selection)
- Esfahanian N. et al. Mortalin: protein partners, biological impacts, pathological roles, and therapeutic opportunities. Frontiers in Cell and Developmental Biology, Feb 2023. URL: https://doi.org/10.3389/fcell.2023.1028519 (esfahanian2023mortalinproteinpartners pages 1-2, esfahanian2023mortalinproteinpartners pages 9-10, esfahanian2023mortalinproteinpartners pages 10-10).
- Jain S., Paz E., Azem A. Hotspots for disease-causing mutations in the mitochondrial TIM23 import complex. Genes, 15:1534, Nov 2024. URL: https://doi.org/10.3390/genes15121534 (PAM centrality of HSPA9; congenital HSPA9 mutations) (jain2024hotspotsfordiseasecausing pages 7-8, jain2024hotspotsfordiseasecausing pages 12-13).
- Heffner A.L., Maio N. Tip of the Iceberg: A New Wave of Iron–Sulfur Cluster Proteins Found in Viruses. Inorganics, 12:34, Jan 2024. URL: https://doi.org/10.20944/preprints202312.1414.v1 (HSPA9/HSCB transfer from ISCU) (heffner2024tipofthe pages 2-4).
- Hong S.-K. et al. Analogs of the Heat Shock Protein 70 Inhibitor MKT-077 Suppress Medullary Thyroid Carcinoma Cells. Int J Mol Sci., 23:1063, Jan 2022. URL: https://doi.org/10.3390/ijms23031063 (preclinical JG-series; cites MKT‑077 Phase I) (hong2022analogsofthe pages 13-13).
- Kaushal S. et al. Synthetic and Natural Inhibitors of Mortalin for Cancer Therapy. Cancers, 16:3470, Oct 2024. URL: https://doi.org/10.3390/cancers16203470 (catalog of inhibitors; translational considerations) (kaushal2024syntheticandnatural pages 16-17).
- Bailone R.L. et al. Mortalin as a biomarker disease and therapeutic target. 2022. Contextual disease and mechanistic overview (bailone2022mortalinasa pages 6-7, bailone2022mortalinasa pages 2-3).

Limitations and open questions
- While multiple reviews and preclinical studies robustly place HSPA9 at the center of mitochondrial import and Fe–S biogenesis, specific structural details for human HSPA9 complexes and comprehensive clinical datasets for HSPA9‑selective inhibitors remain limited in the cited 2023–2024 literature. Further primary studies clarifying regulation by GRPEL1/2 in human systems and advancing clinical programs for mortalin‑directed agents are needed.

References

(esfahanian2023mortalinproteinpartners pages 1-2): Niki Esfahanian, Cole D. Knoblich, Gaven A. Bowman, and Khosrow Rezvani. Mortalin: protein partners, biological impacts, pathological roles, and therapeutic opportunities. Frontiers in Cell and Developmental Biology, Feb 2023. URL: https://doi.org/10.3389/fcell.2023.1028519, doi:10.3389/fcell.2023.1028519. This article has 35 citations and is from a poor quality or predatory journal.
(esfahanian2023mortalinproteinpartners pages 10-11): Niki Esfahanian, Cole D. Knoblich, Gaven A. Bowman, and Khosrow Rezvani. Mortalin: protein partners, biological impacts, pathological roles, and therapeutic opportunities. Frontiers in Cell and Developmental Biology, Feb 2023. URL: https://doi.org/10.3389/fcell.2023.1028519, doi:10.3389/fcell.2023.1028519. This article has 35 citations and is from a poor quality or predatory journal.
(esfahanian2023mortalinproteinpartners pages 9-10): Niki Esfahanian, Cole D. Knoblich, Gaven A. Bowman, and Khosrow Rezvani. Mortalin: protein partners, biological impacts, pathological roles, and therapeutic opportunities. Frontiers in Cell and Developmental Biology, Feb 2023. URL: https://doi.org/10.3389/fcell.2023.1028519, doi:10.3389/fcell.2023.1028519. This article has 35 citations and is from a poor quality or predatory journal.
(jain2024hotspotsfordiseasecausing pages 7-8): Sahil Jain, Eyal Paz, and Abdussalam Azem. Hotspots for disease-causing mutations in the mitochondrial tim23 import complex. Genes, 15:1534, Nov 2024. URL: https://doi.org/10.3390/genes15121534, doi:10.3390/genes15121534. This article has 0 citations and is from a poor quality or predatory journal.
(heffner2024tipofthe pages 2-4): Audrey L. Heffner and Nunziata Maio. Tip of the iceberg: a new wave of iron–sulfur cluster proteins found in viruses. Inorganics, 12:34, Jan 2024. URL: https://doi.org/10.20944/preprints202312.1414.v1, doi:10.20944/preprints202312.1414.v1. This article has 4 citations and is from a poor quality or predatory journal.
(kaushal2024syntheticandnatural pages 16-17): Shruti Kaushal, Samriddhi Gupta, Seyad Shefrin, Dhvani Sandip Vora, Sunil C. Kaul, Durai Sundar, Renu Wadhwa, and Jaspreet Kaur Dhanjal. Synthetic and natural inhibitors of mortalin for cancer therapy. Cancers, 16:3470, Oct 2024. URL: https://doi.org/10.3390/cancers16203470, doi:10.3390/cancers16203470. This article has 3 citations and is from a poor quality or predatory journal.
(hong2022analogsofthe pages 13-13): Seung-Keun Hong, Dmytro Starenki, Oleta T. Johnson, Jason E. Gestwicki, and Jong-In Park. Analogs of the heat shock protein 70 inhibitor mkt-077 suppress medullary thyroid carcinoma cells. International Journal of Molecular Sciences, 23:1063, Jan 2022. URL: https://doi.org/10.3390/ijms23031063, doi:10.3390/ijms23031063. This article has 17 citations and is from a poor quality or predatory journal.
(esfahanian2023mortalinproteinpartners pages 10-10): Niki Esfahanian, Cole D. Knoblich, Gaven A. Bowman, and Khosrow Rezvani. Mortalin: protein partners, biological impacts, pathological roles, and therapeutic opportunities. Frontiers in Cell and Developmental Biology, Feb 2023. URL: https://doi.org/10.3389/fcell.2023.1028519, doi:10.3389/fcell.2023.1028519. This article has 35 citations and is from a poor quality or predatory journal.
(jain2024hotspotsfordiseasecausing pages 12-13): Sahil Jain, Eyal Paz, and Abdussalam Azem. Hotspots for disease-causing mutations in the mitochondrial tim23 import complex. Genes, 15:1534, Nov 2024. URL: https://doi.org/10.3390/genes15121534, doi:10.3390/genes15121534. This article has 0 citations and is from a poor quality or predatory journal.
(bailone2022mortalinasa pages 6-7): RL Bailone, S Fukushima, D Aguiar, and LK Borra. Mortalin as a biomarker disease and therapeutic target. Unknown journal, 2022.
(bailone2022mortalinasa pages 2-3): RL Bailone, S Fukushima, D Aguiar, and LK Borra. Mortalin as a biomarker disease and therapeutic target. Unknown journal, 2022.

Citations

esfahanian2023mortalinproteinpartners pages 9-10
esfahanian2023mortalinproteinpartners pages 10-11
jain2024hotspotsfordiseasecausing pages 7-8
heffner2024tipofthe pages 2-4
hong2022analogsofthe pages 13-13
kaushal2024syntheticandnatural pages 16-17
esfahanian2023mortalinproteinpartners pages 1-2
esfahanian2023mortalinproteinpartners pages 10-10
jain2024hotspotsfordiseasecausing pages 12-13
bailone2022mortalinasa pages 6-7
bailone2022mortalinasa pages 2-3
https://doi.org/10.3390/genes15121534
https://doi.org/10.20944/preprints202312.1414.v1
https://doi.org/10.3390/cancers16203470
https://doi.org/10.3390/ijms23031063
https://doi.org/10.3389/fcell.2023.1028519
https://doi.org/10.3389/fcell.2023.1028519,
https://doi.org/10.3390/genes15121534,
https://doi.org/10.20944/preprints202312.1414.v1,
https://doi.org/10.3390/cancers16203470,
https://doi.org/10.3390/ijms23031063,

📄 View Raw YAML

id: P38646
gene_symbol: HSPA9
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'TODO: Add description for HSPA9'
existing_annotations:
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0031072
      label: heat shock protein binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0044183
      label: protein folding chaperone
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0042026
      label: protein refolding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0006457
      label: protein folding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0051082
      label: unfolded protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: GO:0051082 is currently under obsoletion review (go-ontology#30962) because it 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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0044183
          label: protein folding chaperone
      supported_by:
        - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
          supporting_text: 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.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15657067
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:15657067
          supporting_text: Epub 2005 Jan 17. Phosphotyrosine signaling networks 
            in epidermal growth factor receptor overexpressing squamous 
            carcinoma cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17184779
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:17184779
          supporting_text: 2006 Dec 13. Identification of differential proteins 
            in nasopharyngeal carcinoma cells with p53 silence by proteome 
            analysis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20029029
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20029029
          supporting_text: Regulation of epidermal growth factor receptor 
            trafficking by lysine deacetylase HDAC6.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20153329
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20153329
          supporting_text: 2010 Feb 12. Reconstitution of the mitochondrial 
            Hsp70 (mortalin)-p53 interaction using purified 
            proteins--identification of additional interacting regions.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20195357
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20195357
          supporting_text: A comprehensive resource of interacting protein 
            regions for refining human transcription factor networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22340593
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:22340593
          supporting_text: Aurora kinase-A inactivates DNA damage-induced 
            apoptosis and spindle assembly checkpoint response functions of p73.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22726440
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:22726440
          supporting_text: p53 opens the mitochondrial permeability transition 
            pore to trigger necrosis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24189400
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:24189400
          supporting_text: Perturbation of the mutated EGFR interactome 
            identifies vulnerabilities and resistance mechanisms.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24606901
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:24606901
          supporting_text: Cochaperone binding to LYR motifs confers specificity
            of iron sulfur cluster delivery.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome 
            network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27107014
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:27107014
          supporting_text: An inter-species protein-protein interaction network 
            across vast evolutionary distance.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27607350
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:27607350
          supporting_text: Characterization of the Translationally Controlled 
            Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in 
            Human Cancer Cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28380382
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:28380382
          supporting_text: A Single Adaptable Cochaperone-Scaffold Complex 
            Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain
            Complexes I-III.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30021884
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:30021884
          supporting_text: Epub 2018 Jul 18. Histone Interaction Landscapes 
            Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31978385
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:31978385
          supporting_text: Epub 2020 Jan 21. TGR5 promotes cholangiocarcinoma by
            interacting with mortalin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31980649
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:31980649
          supporting_text: Extensive rewiring of the EGFR network in colorectal 
            cancer cells expressing transforming levels of KRAS(G13D).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32807793
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:32807793
          supporting_text: OSMR controls glioma stem cell respiration and 
            confers resistance of glioblastoma to ionizing radiation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:1902037
      label: negative regulation of hematopoietic stem cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:1903707
      label: negative regulation of hemopoiesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: NAS
    original_reference_id: PMID:10339406
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:10339406
          supporting_text: Genetic and structural characterization of the human 
            mitochondrial inner membrane translocase.
  - term:
      id: GO:0006886
      label: intracellular protein transport
    evidence_type: NAS
    original_reference_id: PMID:10339406
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:10339406
          supporting_text: Genetic and structural characterization of the human 
            mitochondrial inner membrane translocase.
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IDA
    original_reference_id: PMID:18632665
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:18632665
          supporting_text: 2008 Jul 16. The human escort protein Hep binds to 
            the ATPase domain of mitochondrial hsp70 and regulates ATP 
            hydrolysis.
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IDA
    original_reference_id: PMID:25615450
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:25615450
          supporting_text: 'eCollection 2015. Human mitochondrial Hsp70 (mortalin):
            shedding light on ATPase activity, interaction with adenosine nucleotides,
            solution structure and domain organization.'
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:34800366
          supporting_text: Epub 2021 Nov 19. Quantitative high-confidence human 
            mitochondrial proteome and its dynamics in cellular context.
  - term:
      id: GO:0036444
      label: calcium import into the mitochondrion
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IDA
    original_reference_id: PMID:7865888
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:7865888
          supporting_text: PBP74, a new member of the mammalian 70-kDa heat 
            shock protein family, is a mitochondrial protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24625977
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:24625977
          supporting_text: Ubiquitin-like (UBX)-domain-containing protein, 
            UBXN2A, promotes cell death by interfering with the p53-Mortalin 
            interactions in colon cancer cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26634371
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26634371
          supporting_text: Epub 2015 Dec 4. Structural studies of UBXN2A and 
            mortalin interaction and the putative role of silenced UBXN2A in 
            preventing response to chemotherapy.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23940031
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23940031
          supporting_text: 2013 Aug 12. 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).
  - term:
      id: GO:0001401
      label: SAM complex
    evidence_type: HDA
    original_reference_id: PMID:26477565
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26477565
          supporting_text: Evolution and structural organization of the 
            mitochondrial contact site (MICOS) complex and the mitochondrial 
            intermembrane space bridging (MIB) complex.
  - term:
      id: GO:0007007
      label: inner mitochondrial membrane organization
    evidence_type: IC
    original_reference_id: PMID:26477565
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26477565
          supporting_text: Evolution and structural organization of the 
            mitochondrial contact site (MICOS) complex and the mitochondrial 
            intermembrane space bridging (MIB) complex.
  - term:
      id: GO:0140275
      label: MIB complex
    evidence_type: HDA
    original_reference_id: PMID:26477565
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26477565
          supporting_text: Evolution and structural organization of the 
            mitochondrial contact site (MICOS) complex and the mitochondrial 
            intermembrane space bridging (MIB) complex.
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IMP
    original_reference_id: PMID:26702583
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26702583
          supporting_text: Dec 17. Mitochondrial Hspa9/Mortalin regulates 
            erythroid differentiation via iron-sulfur cluster assembly.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26702583
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26702583
          supporting_text: Dec 17. Mitochondrial Hspa9/Mortalin regulates 
            erythroid differentiation via iron-sulfur cluster assembly.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:26702583
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26702583
          supporting_text: Dec 17. Mitochondrial Hspa9/Mortalin regulates 
            erythroid differentiation via iron-sulfur cluster assembly.
  - term:
      id: GO:0045646
      label: regulation of erythrocyte differentiation
    evidence_type: IMP
    original_reference_id: PMID:26702583
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:26702583
          supporting_text: Dec 17. Mitochondrial Hspa9/Mortalin regulates 
            erythroid differentiation via iron-sulfur cluster assembly.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23541579
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:23541579
          supporting_text: Extracellular heat shock protein A9 is a novel 
            interaction partner of podoplanin in oral squamous cell carcinoma 
            cells.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8950389
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838035
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838081
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838093
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838289
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9856627
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
  - term:
      id: GO:0030218
      label: erythrocyte differentiation
    evidence_type: IMP
    original_reference_id: PMID:21123823
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:21123823
          supporting_text: Dec 1. Knockdown of Hspa9, a del(5q31.2) gene, 
            results in a decrease in hematopoietic progenitors in mice.
  - term:
      id: GO:0045647
      label: negative regulation of erythrocyte differentiation
    evidence_type: IMP
    original_reference_id: PMID:21123823
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:21123823
          supporting_text: Dec 1. Knockdown of Hspa9, a del(5q31.2) gene, 
            results in a decrease in hematopoietic progenitors in mice.
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:19725078
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:19725078
          supporting_text: Proteomic analysis of increased Parkin expression and
            its interactants provides evidence for a role in modulation of 
            mitochondrial function.
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:21753002
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:21753002
          supporting_text: Parkin interacts with Ambra1 to induce mitophagy.
  - term:
      id: GO:0005925
      label: focal adhesion
    evidence_type: HDA
    original_reference_id: PMID:21423176
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:21423176
          supporting_text: Analysis of the myosin-II-responsive focal adhesion 
            proteome reveals a role for β-Pix in negative regulation of focal 
            adhesion maturation.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22658674
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:22658674
          supporting_text: May 31. Insights into RNA biology from an atlas of 
            mammalian mRNA-binding proteins.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22681889
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:22681889
          supporting_text: The mRNA-bound proteome and its global occupancy 
            profile on protein-coding transcripts.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:20458337
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20458337
          supporting_text: 2010 May 11. MHC class II-associated proteins in 
            B-cell exosomes and potential functional implications for exosome 
            biogenesis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20668094
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:20668094
          supporting_text: Jul 28. Characterization of the human HSC20, an 
            unusual DnaJ type III protein, involved in iron-sulfur cluster 
            biogenesis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15520177
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:15520177
          supporting_text: Tid1, the human homologue of a Drosophila tumor 
            suppressor, reduces the malignant activity of ErbB-2 in carcinoma 
            cells.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10411904
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:10411904
          supporting_text: TID1, a human homolog of the Drosophila tumor 
            suppressor l(2)tid, encodes two mitochondrial modulators of 
            apoptosis with opposing functions.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:7896880
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:7896880
          supporting_text: The intracellular distribution and pattern of 
            expression of Mcl-1 overlap with, but are not identical to, those of
            Bcl-2.
  - term:
      id: GO:0042645
      label: mitochondrial nucleoid
    evidence_type: IDA
    original_reference_id: PMID:18063578
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:18063578
          supporting_text: 2007 Dec 6. The layered structure of human 
            mitochondrial DNA nucleoids.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: TAS
    original_reference_id: PMID:16130169
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:16130169
          supporting_text: Proteomics of human umbilical vein endothelial cells 
            applied to etoposide-induced apoptosis.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: TAS
    original_reference_id: PMID:16130169
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:16130169
          supporting_text: Proteomics of human umbilical vein endothelial cells 
            applied to etoposide-induced apoptosis.
  - term:
      id: GO:0051082
      label: unfolded protein binding
    evidence_type: TAS
    original_reference_id: PMID:16130169
    review:
      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. Given GO:0051082 obsoletion review,
        this annotation should be remapped.
      action: MODIFY
      reason: HSPA9 is a mitochondrial Hsp70 foldase chaperone (mtHsp70/mortalin). The GO:0051082 label
        is too generic and is being reviewed for obsoletion; GO:0044183 better captures the molecular
        mechanism.
      proposed_replacement_terms:
        - id: GO:0044183
          label: protein folding chaperone
      supported_by:
        - reference_id: PMID:16130169
          supporting_text: Proteomics of human umbilical vein endothelial cells 
            applied to etoposide-induced apoptosis.
        - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
          supporting_text: 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).
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: TAS
    original_reference_id: PMID:7684501
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:7684501
          supporting_text: Cloning of the gene encoding peptide-binding protein 
            74 shows that it is a new member of the heat shock protein 70 
            family.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: TAS
    original_reference_id: PMID:7829505
    review:
      summary: 'TODO: Review this GOA annotation'
      action: PENDING
      supported_by:
        - reference_id: PMID:7829505
          supporting_text: Cloning and subcellular localization of human 
            mitochondrial hsp70.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    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:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    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:10339406
    title: Genetic and structural characterization of the human mitochondrial 
      inner membrane translocase.
    findings: []
  - id: PMID:10411904
    title: TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, 
      encodes two mitochondrial modulators of apoptosis with opposing functions.
    findings: []
  - id: PMID:15520177
    title: Tid1, the human homologue of a Drosophila tumor suppressor, reduces 
      the malignant activity of ErbB-2 in carcinoma cells.
    findings: []
  - id: PMID:15657067
    title: Phosphotyrosine signaling networks in epidermal growth factor 
      receptor overexpressing squamous carcinoma cells.
    findings: []
  - id: PMID:16130169
    title: Proteomics of human umbilical vein endothelial cells applied to 
      etoposide-induced apoptosis.
    findings: []
  - id: PMID:17184779
    title: Identification of differential proteins in nasopharyngeal carcinoma 
      cells with p53 silence by proteome analysis.
    findings: []
  - id: PMID:18063578
    title: The layered structure of human mitochondrial DNA nucleoids.
    findings: []
  - id: PMID:18632665
    title: The human escort protein Hep binds to the ATPase domain of 
      mitochondrial hsp70 and regulates ATP hydrolysis.
    findings: []
  - id: PMID:19725078
    title: Proteomic analysis of increased Parkin expression and its 
      interactants provides evidence for a role in modulation of mitochondrial 
      function.
    findings: []
  - id: PMID:20029029
    title: Regulation of epidermal growth factor receptor trafficking by lysine 
      deacetylase HDAC6.
    findings: []
  - id: PMID:20153329
    title: Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction 
      using purified proteins--identification of additional interacting regions.
    findings: []
  - id: PMID:20195357
    title: A comprehensive resource of interacting protein regions for refining 
      human transcription factor networks.
    findings: []
  - id: PMID:20458337
    title: MHC class II-associated proteins in B-cell exosomes and potential 
      functional implications for exosome biogenesis.
    findings: []
  - id: PMID:20668094
    title: Characterization of the human HSC20, an unusual DnaJ type III 
      protein, involved in iron-sulfur cluster biogenesis.
    findings: []
  - id: PMID:21123823
    title: Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in 
      hematopoietic progenitors in mice.
    findings: []
  - id: PMID:21423176
    title: "Analysis of the myosin-II-responsive focal adhesion proteome reveals a
      role for β-Pix in negative regulation of focal adhesion maturation."
    findings: []
  - id: PMID:21753002
    title: Parkin interacts with Ambra1 to induce mitophagy.
    findings: []
  - id: PMID:22340593
    title: Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle 
      assembly checkpoint response functions of p73.
    findings: []
  - id: PMID:22658674
    title: Insights into RNA biology from an atlas of mammalian mRNA-binding 
      proteins.
    findings: []
  - id: PMID:22681889
    title: The mRNA-bound proteome and its global occupancy profile on 
      protein-coding transcripts.
    findings: []
  - id: PMID:22726440
    title: p53 opens the mitochondrial permeability transition pore to trigger 
      necrosis.
    findings: []
  - id: PMID:23541579
    title: Extracellular heat shock protein A9 is a novel interaction partner of
      podoplanin in oral squamous cell carcinoma cells.
    findings: []
  - id: PMID:23940031
    title: 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).
    findings: []
  - id: PMID:24189400
    title: Perturbation of the mutated EGFR interactome identifies 
      vulnerabilities and resistance mechanisms.
    findings: []
  - id: PMID:24606901
    title: Cochaperone binding to LYR motifs confers specificity of iron sulfur 
      cluster delivery.
    findings: []
  - id: PMID:24625977
    title: Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell
      death by interfering with the p53-Mortalin interactions in colon cancer 
      cells.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:25615450
    title: 'Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity,
      interaction with adenosine nucleotides, solution structure and domain organization.'
    findings: []
  - id: PMID:26477565
    title: Evolution and structural organization of the mitochondrial contact 
      site (MICOS) complex and the mitochondrial intermembrane space bridging 
      (MIB) complex.
    findings: []
  - id: PMID:26634371
    title: Structural studies of UBXN2A and mortalin interaction and the 
      putative role of silenced UBXN2A in preventing response to chemotherapy.
    findings: []
  - id: PMID:26702583
    title: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via 
      iron-sulfur cluster assembly.
    findings: []
  - id: PMID:27107014
    title: An inter-species protein-protein interaction network across vast 
      evolutionary distance.
    findings: []
  - id: PMID:27607350
    title: Characterization of the Translationally Controlled Tumor Protein 
      (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells.
    findings: []
  - id: PMID:28380382
    title: A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent 
      Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:30021884
    title: Histone Interaction Landscapes Visualized by Crosslinking Mass 
      Spectrometry in Intact Cell Nuclei.
    findings: []
  - id: PMID:31978385
    title: TGR5 promotes cholangiocarcinoma by interacting with mortalin.
    findings: []
  - id: PMID:31980649
    title: Extensive rewiring of the EGFR network in colorectal cancer cells 
      expressing transforming levels of KRAS(G13D).
    findings: []
  - id: PMID:32807793
    title: OSMR controls glioma stem cell respiration and confers resistance of 
      glioblastoma to ionizing radiation.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its 
      dynamics in cellular context.
    findings: []
  - id: PMID:7684501
    title: Cloning of the gene encoding peptide-binding protein 74 shows that it
      is a new member of the heat shock protein 70 family.
    findings: []
  - id: PMID:7829505
    title: Cloning and subcellular localization of human mitochondrial hsp70.
    findings: []
  - id: PMID:7865888
    title: PBP74, a new member of the mammalian 70-kDa heat shock protein 
      family, is a mitochondrial protein.
    findings: []
  - id: PMID:7896880
    title: The intracellular distribution and pattern of expression of Mcl-1 
      overlap with, but are not identical to, those of Bcl-2.
    findings: []
  - id: Reactome:R-HSA-8950389
    title: Expression of Stress-70 protein, mitochondrial
    findings: []
  - id: Reactome:R-HSA-9838035
    title: CLPXP binds mitochondrial matrix proteins
    findings: []
  - id: Reactome:R-HSA-9838081
    title: LONP1 degrades mitochondrial matrix proteins
    findings: []
  - id: Reactome:R-HSA-9838093
    title: LONP1 binds mitochondrial matrix proteins
    findings: []
  - id: Reactome:R-HSA-9838289
    title: CLPXP degrades mitochondrial matrix proteins
    findings: []
  - id: Reactome:R-HSA-9856627
    title: ATF5 and HSF1 trimer activate expression of HSPA9 (mtHSP70)
    findings: []
  - id: file:human/HSPA9/HSPA9-deep-research-falcon.md
    title: Deep research report on HSPA9
    findings: []
tags:
  - iron-sulfur-cluster-biogenesis

HSPA9

Gene Description

Existing Annotations Review

References

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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