GrpE protein homolog 2 (mt-GrpE#2) is a mitochondrial matrix GrpE-family co-chaperone in the HSPA9/mtHsp70 system. It acts as an adenyl-nucleotide exchange factor and probable PAM import-motor component, and the two mammalian paralogs divide the labour: GRPEL1 is the dominant housekeeping nucleotide-exchange factor for ADP-bound mtHsp70, while GRPEL2 is weaker and more redox/stress-modulated. Grpel2 therefore supports mitochondrial matrix proteostasis, protein import/folding, and stress adaptation rather than acting as the sole or primary mtHsp70 NEF under basal conditions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000774 adenyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Grpel2 is a GrpE-family co-chaperone in the mitochondrial Hsp70 system. The nucleotide-exchange annotation remains valid, but Falcon-reviewed recent work indicates GRPEL2 has weaker ADP-mtHsp70 binding than GRPEL1 and is likely stress/redox-modulated rather than the dominant housekeeping NEF. Reason: This is the closest available molecular-function term for the conserved GrpE role. The annotation should be retained with the paralog-specific caveat that GRPEL2 appears conditional/stress-modulated relative to GRPEL1. Supporting Evidence: PMID:9694873 The functional integrity of mt-GrpE#1 and #2 was verified by their ability to specifically interact with and stimulate the ATPase activity of mammalian mitochondrial Hsp70 (mt-Hsp70). file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0001405 PAM complex, Tim23 associated import motor | IBA GO_REF:0000033 | ACCEPT | Summary: Grpel2 is annotated as a component of the PAM complex by phylogenetic inference. UniProt states (by similarity) that it is a probable component of the PAM complex composed of mt-HSP70, GRPEL1 or GRPEL2, TIMM44, PAM16, and DNAJC19. The yeast ortholog (MGE1/YOR232W) is a well-established PAM complex component. This annotation is consistent with the known biology. Reason: GrpE proteins function as nucleotide exchange factors within the PAM import motor complex. The IBA annotation based on phylogenetic inference from the yeast ortholog is well-supported by structural and functional conservation of the PAM complex across eukaryotes. UniProt confirms this localization by similarity. Supporting Evidence: file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0030150 protein import into mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: As a component of the PAM complex, Grpel2 participates in protein import into the mitochondrial matrix. The nucleotide exchange activity of GrpE is essential for the mt-Hsp70 ATPase cycle that drives translocation of preproteins through the TIM23 channel. This is a core biological process for this protein, well-supported by IBA from phylogenetic inference. Reason: Protein import into the mitochondrial matrix is the primary biological process function of the PAM complex. Grpel2 as a NEF for mt-Hsp70 plays an essential role in this process. The IBA annotation is phylogenetically sound and consistent with UniProt functional description. Supporting Evidence: file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0051082 unfolded protein binding | IBA GO_REF:0000033 | MODIFY | Summary: Unfolded protein binding is not the right molecular-function term for Grpel2. Grpel2 is a GrpE-family nucleotide exchange factor for mitochondrial Hsp70, not a direct unfolded-substrate binding chaperone. Reason: GRPEL2 is a mitochondrial HSPA9/mtHsp70 nucleotide-exchange co-chaperone, not an independent unfolded-substrate binding foldase. Replace with the directly supported nucleotide-exchange molecular function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1334416 · mouse Grpel2 (the review target itself) SUPPORTS TRANSFER The target's own MGI record is one of the IBD seeds, so the transfer restates curated target-level evidence rather than importing a foreign claim. The fault is in the term: GRPEL2 is a nucleotide-exchange factor acting on mtHsp70, so substrate binding is the chaperone's role, not the exchange factor's - and GO:0051082 is now obsolete. PANTHER:PTN000478264 SUPPORTS TRANSFER The GrpE-family node of PTHR21237 (PANTHER name "GRPE PROTEIN"). The local PAINT cache carries this node only for GO:0000774, not for the obsolete GO:0051082, so the WITH/FROM is the only evidence available for this row. That the cached IBD is for adenyl-nucleotide exchange factor activity is itself consistent with the MODIFY: the node's inherited property is exchange-factor activity, which is the replacement term proposed here. UniProtKB:Q9HAV7 · human GRPEL1 SUPPORTS TRANSFER The human PARALOG, not the ortholog - GRPEL1 rather than GRPEL2 (genes/human/GRPEL1 is ID GRPE1_HUMAN / AC Q9HAV7; projects/TOP_NOTS.md also lists Q9HAV7 as GRPEL1). It is a co-seed of the same GrpE-family node, so it supports the family-level transfer - but this repository has already adjudicated the donor's own annotation to this very term: projects/UNFOLDED_PROTEIN_BINDING.md records GRPEL1's GO:0051082 as REMOVE, "Regulates HSP70 nucleotide cycle, does not bind unfolded substrate directly", and assigns GO:0000774 as its core MF. So the propagation carries a claim its own donor has been judged not to support, which strengthens rather than weakens the MODIFY - and GO:0000774 is the same replacement that project assigns. Proposed replacements: adenyl-nucleotide exchange factor activity Supporting Evidence: file:mouse/Grpel2/Grpel2-notes.md specifically interact with and stimulate the ATPase activity of mammalian mitochondrial Hsp70 file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0000774 adenyl-nucleotide exchange factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Grpel2 is a GrpE-family co-chaperone in the mitochondrial Hsp70 system. The nucleotide-exchange annotation remains valid, but Falcon-reviewed recent work indicates GRPEL2 has weaker ADP-mtHsp70 binding than GRPEL1 and is likely stress/redox-modulated rather than the dominant housekeeping NEF. Reason: This is the closest available molecular-function term for the conserved GrpE role. The annotation should be retained with the paralog-specific caveat that GRPEL2 appears conditional/stress-modulated relative to GRPEL1. Supporting Evidence: file:mouse/Grpel2/Grpel2-notes.md Core evidence: Grpel2 is a mitochondrial GrpE-family nucleotide exchange factor file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location mapping. UniProt states Grpel2 localizes to the mitochondrion matrix. The protein has a mitochondrial transit peptide (residues 1-31) and functions within the matrix as part of the PAM complex. Reason: Mitochondrial matrix localization is well-supported by the presence of a mitochondrial transit peptide, the protein's function as a NEF for matrix-localized mt-Hsp70, and its role in the PAM complex. More specific than GO:0005739 (mitochondrion) and accurately reflects the sub-organellar localization. Supporting Evidence: file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0006457 protein folding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro mapping. Grpel2 participates in protein folding indirectly as a co-chaperone for mt-Hsp70. However, its more specific biological process role is in protein import into the mitochondrial matrix (GO:0030150). Protein folding is a broader acceptable annotation but not the most informative. Reason: While protein import into the mitochondrial matrix is the more specific process, Grpel2 does participate in protein folding through its role in regulating mt-Hsp70. The IEA annotation is not incorrect and provides complementary biological context to GO:0030150. As an IEA it is acceptably general. Supporting Evidence: file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: IEA annotation from InterPro mapping. Bacterial GrpE forms homodimers, and this is a conserved feature of GrpE-family proteins. However, homodimerization is a structural property rather than a functional molecular activity of interest, and it has not been directly demonstrated for mouse Grpel2. Reason: While GrpE-family proteins are known to form homodimers, this annotation describes a structural feature rather than the functional molecular activity. Homodimerization is not experimentally verified for Grpel2 specifically, and this IEA may be an over-extension from bacterial GrpE structural data. The core molecular function is GO:0000774 (adenyl-nucleotide exchange factor activity). |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro mapping. Grpel2 does bind mt-Hsp70 (a protein-folding chaperone) as part of its nucleotide exchange function. Naylor et al. (PMID:9694873) showed that the GrpE-like proteins bound to E. coli DnaK and to mammalian mt-Hsp70. Reason: This annotation correctly captures the binding interaction between Grpel2 and mt-Hsp70. As a nucleotide exchange factor, Grpel2 must physically bind to Hsp70 to catalyze ADP release. This is experimentally supported (PMID:9694873). Supporting Evidence: PMID:9694873 Investigation of the microsomal and two mitochondrial GrpE-like proteins revealed that they bound specifically to Escherichia coli DnaK, and the complexes formed were not disrupted in the presence of 0.5 M salt but were readily dissociated in the presence of 5 mM ATP. file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0005739 mitochondrion | ISO GO_REF:0000119 | ACCEPT | Summary: ISO annotation transferred from the human ortholog (UniProtKB:Q8TAA5, GRPEL2). Mitochondrial localization is well-established for this protein family and supported by multiple lines of evidence including transit peptide, proteomics, and functional data. Reason: Mitochondrial localization is strongly supported by the mitochondrial transit peptide (residues 1-31), proteomic detection in mitochondrial preparations (PMID:18614015, PMID:14651853), and functional role in the mitochondrial PAM complex. The ISO transfer from human ortholog is well-justified. Supporting Evidence: file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara ortholog transfer (from human GRPEL2, UniProtKB:Q8TAA5). Consistent with all other evidence for mitochondrial localization. Reason: Redundant with the ISO annotation for the same term but from a different evidence pipeline. Mitochondrial localization is well-established. Supporting Evidence: file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0005739 mitochondrion | HDA PMID:18614015 A mitochondrial protein compendium elucidates complex I dise... | ACCEPT | Summary: HDA annotation from the MitoCarta mitochondrial protein compendium (Pagliarini et al. 2008). This large-scale proteomics study used mass spectrometry, GFP tagging, and machine learning to create a compendium of 1098 mitochondrial genes across 14 mouse tissues. Reason: The MitoCarta compendium is a high-quality proteomics dataset that provides strong experimental support for mitochondrial localization. Detection by mass spectrometry in purified mitochondrial preparations is direct evidence for this cellular component annotation. Supporting Evidence: PMID:18614015 We performed mass spectrometry, GFP tagging, and machine learning to create a mitochondrial compendium of 1098 genes and their protein expression across 14 mouse tissues. file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0005739 mitochondrion | HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity... | ACCEPT | Summary: HDA annotation from Mootha et al. (2003), an integrated proteomic survey of mitochondria from mouse brain, heart, kidney, and liver. This study produced a list of 591 mitochondrial proteins. Reason: Detection in a large-scale mitochondrial proteomics study provides direct evidence for mitochondrial localization. Consistent with all other localization evidence. Supporting Evidence: PMID:14651853 To explore its molecular composition, we performed a proteomic survey of mitochondria from mouse brain, heart, kidney, and liver and combined the results with existing gene annotations to produce a list of 591 mitochondrial proteins, including 163 proteins not previously associated with this organelle. file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
| GO:0005743 mitochondrial inner membrane | HDA PMID:12865426 Proteomic analysis of the mouse liver mitochondrial inner me... | MODIFY | Summary: HDA annotation from Da Cruz et al. (2003), a proteomic analysis of purified mouse liver mitochondrial inner membrane. The study identified 182 proteins in the inner membrane fraction. However, Grpel2 is a soluble matrix protein that associates with the PAM complex at the inner membrane. Detection in the inner membrane fraction may reflect its association with the membrane-bound TIM23 complex rather than intrinsic membrane localization. Reason: HDA detection in an inner-membrane fraction can be explained by peripheral PAM/TIM23 association, but the local evidence supports GRPEL2 primarily as a soluble mitochondrial matrix nucleotide-exchange factor rather than an inner-membrane component. Replace with the matrix localization. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:12865426 We have focused our study on the identification of proteins of the mitochondrial inner membrane (MIM)... This procedure allowed us to identify 182 proteins that are involved in several biochemical processes, such as the electron transport machinery, the protein import machinery, protein synthesis, lipid metabolism, and ion or substrate transport. |
| GO:0051082 unfolded protein binding | IDA PMID:9694873 Evidence for the existence of distinct mammalian cytosolic, ... | MODIFY | Summary: Unfolded protein binding is not the right molecular-function term for Grpel2. Grpel2 is a GrpE-family nucleotide exchange factor for mitochondrial Hsp70, not a direct unfolded-substrate binding chaperone. Reason: GRPEL2 is a mitochondrial HSPA9/mtHsp70 nucleotide-exchange co-chaperone, not an independent unfolded-substrate binding foldase. Replace with the directly supported nucleotide-exchange molecular function. Proposed replacements: adenyl-nucleotide exchange factor activity Supporting Evidence: file:mouse/Grpel2/Grpel2-notes.md specifically interact with and stimulate the ATPase activity of mammalian mitochondrial Hsp70 file:mouse/Grpel2/Grpel2-deep-research-falcon.md GRPEL2 is a mitochondrial matrix GrpE-family co-chaperone in the mtHSP70/HSPA9 system; GRPEL2 appears weaker and more redox/stress-modulated than GRPEL1 |
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