TIMM50

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0030150 protein import into mitochondrial matrix	IBA GO_REF:0000033	ACCEPT	Summary: Correct and core. TIMM50 is the TIM23 presequence receptor/gatekeeper needed for import of transit peptide-containing precursors through the inner membrane toward the matrix or IMM sorting pathway. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 primarily acts on presequence-containing precursor proteins, which constitute a large fraction of the mitochondrial proteome and are imported through the TIM23 pathway for matrix delivery or IMM insertion. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported.
GO:0005744 TIM23 mitochondrial import inner membrane translocase complex	IBA GO_REF:0000033	ACCEPT	Summary: Correct and core. TIMM50 is a core TIM23 complex subunit that directly coordinates presequence handoff and channel gating. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported. PMID:15044455 complex with human Tim23. Down-regulation of human Tim50 expression by RNA
GO:0004722 protein serine/threonine phosphatase activity	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Human TIMM50 was reported to hydrolyse pNPP and phosphotyrosine and phosphothreonine peptides in vitro (Guo et al. 2004). The full text shows this rests on one assay of GST fusions purified from E. coli, with no catalytic-site mutant and no physiological substrate. TIMM50 lacks the catalytic motif of FCP/SCP phosphatases, and its established role is TIM23 presequence receptor/gatekeeper. Reason: The reported activity is a real in vitro observation, so the annotation is not plainly wrong, but it is weak evidence that phosphatase activity is a function of this protein. (1) The assay used GST fusions purified from E. coli; the controls were GST alone and the N-terminal targeting fragment, and no catalytic-residue mutant was tested, so a co-purifying bacterial phosphatase is not excluded. (2) Activity peaked at pH 4.0-6.0 and declined sharply at basic pH. (3) No physiological substrate was shown; dephosphorylation of Bcl-2 family proteins is offered in the Discussion only as speculation. (4) The CTD-like domain lacks the D-x-D-x-(T/V) catalytic motif of FCP/SCP phosphatases (TIMM50-bioinformatics/RESULTS.md; the T. brucei Tim50 control has it), and the authors note that yeast Tim50 lacks the activity. PAINT blocks the ancestral phosphatase IBD for the whole Tim50 clade, and the PTHR12210 family review judges that block LOSS_SUPPORTED. UniProt likewise says the activity may not be relevant in vivo. Supporting Evidence: PMID:15044455 To test this possibility we expressed N-terminal GST-tagged full-length or truncated human Tim50 in bacteria PMID:15044455 The human Tim50 phosphatase activity displayed a bell-shaped pH profile with an optimum activity around pH 4.0–6.0. Phosphatase activity declined sharply at basic pH PMID:15044455 It is tempting to speculate that in addition to its translocase activity, human Tim50 might also function as a phosphatase for certain mitochondrial proteins PMID:15044455 while yeast Tim50 was reported not to have such an activity file:human/TIMM50/TIMM50-bioinformatics/RESULTS.md \| Q3ZCQ8 \| Homo sapiens \| TIMM50 \| 353 \| none \| file:human/TIMM50/TIMM50-deep-research-falcon.md Therefore, based on available evidence, the primary validated function remains protein import receptor/gating, not a defined metabolic reaction with established substrates.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: Correct. Canonical TIMM50 is a single-pass mitochondrial inner membrane protein with its receptor/gating domain exposed to the intermembrane space. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 is a single-pass IMM protein with an N-terminal mitochondrial targeting sequence, a transmembrane anchor, and a large IMS-exposed hydrophilic domain that mediates receptor/gating functions.
GO:0016607 nuclear speck	IEA Q3ZCQ8-2 GO_REF:0000044	KEEP AS NON CORE	Summary: Supported for the Tim50a isoform, but not the core function of the canonical mitochondrial TIMM50 protein. Reason: Track as isoform-specific, non-core nuclear localization; canonical TIMM50 function is mitochondrial TIM23 import. Supporting Evidence: PMID:16008839 cytoplasm and mitochondria, Tim50a is strictly nuclear and is enriched in
GO:0005515 protein binding	IPI PMID:12620389 Novel raf kinase protein-protein interactions found by an ex...	MARK AS OVER ANNOTATED	Summary: Protein binding is true but uninformative for TIMM50. The biologically meaningful interaction context is TIM23 presequence receptor/gating and TIMM23/TIM17 complex membership. Reason: Replace generic interaction capture with TIM23 complex membership and presequence/targeting-sequence binding where supported. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported.
GO:0005515 protein binding	IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo...	MARK AS OVER ANNOTATED	Summary: Protein binding is true but uninformative for TIMM50. The biologically meaningful interaction context is TIM23 presequence receptor/gating and TIMM23/TIM17 complex membership. Reason: Replace generic interaction capture with TIM23 complex membership and presequence/targeting-sequence binding where supported. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	MARK AS OVER ANNOTATED	Summary: Protein binding is true but uninformative for TIMM50. The biologically meaningful interaction context is TIM23 presequence receptor/gating and TIMM23/TIM17 complex membership. Reason: Replace generic interaction capture with TIM23 complex membership and presequence/targeting-sequence binding where supported. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported.
GO:0005515 protein binding	IPI PMID:37045861 Interactome dynamics of RAF1-BRAF kinase monomers and dimers...	MARK AS OVER ANNOTATED	Summary: Protein binding is true but uninformative for TIMM50. The biologically meaningful interaction context is TIM23 presequence receptor/gating and TIMM23/TIM17 complex membership. Reason: Replace generic interaction capture with TIM23 complex membership and presequence/targeting-sequence binding where supported. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported.
GO:0005743 mitochondrial inner membrane	IDA PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	ACCEPT	Summary: Correct. Canonical TIMM50 is a single-pass mitochondrial inner membrane protein with its receptor/gating domain exposed to the intermembrane space. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 is a single-pass IMM protein with an N-terminal mitochondrial targeting sequence, a transmembrane anchor, and a large IMS-exposed hydrophilic domain that mediates receptor/gating functions.
GO:0005743 mitochondrial inner membrane	NAS PMID:10339406 Genetic and structural characterization of the human mitocho...	ACCEPT	Summary: Correct. Canonical TIMM50 is a single-pass mitochondrial inner membrane protein with its receptor/gating domain exposed to the intermembrane space. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 is a single-pass IMM protein with an N-terminal mitochondrial targeting sequence, a transmembrane anchor, and a large IMS-exposed hydrophilic domain that mediates receptor/gating functions.
GO:0005744 TIM23 mitochondrial import inner membrane translocase complex	NAS PMID:10339406 Genetic and structural characterization of the human mitocho...	ACCEPT	Summary: Correct and core. TIMM50 is a core TIM23 complex subunit that directly coordinates presequence handoff and channel gating. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported. PMID:15044455 complex with human Tim23. Down-regulation of human Tim50 expression by RNA
GO:0006886 intracellular protein transport	NAS PMID:10339406 Genetic and structural characterization of the human mitocho...	MARK AS OVER ANNOTATED	Summary: Correct pathway family but too broad. TIMM50 specifically mediates TIM23-dependent mitochondrial presequence protein import rather than general intracellular protein transport. Reason: Use mitochondrial matrix import/TIM23 terms instead of generic intracellular transport. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 primarily acts on presequence-containing precursor proteins, which constitute a large fraction of the mitochondrial proteome and are imported through the TIM23 pathway for matrix delivery or IMM insertion. file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	MARK AS OVER ANNOTATED	Summary: Broad nuclear localization is less informative than the isoform-specific nuclear speck evidence for Tim50a and is not the canonical TIMM50 localization. Reason: Use isoform-specific nuclear speck annotation for Tim50a; canonical TIMM50 is an inner mitochondrial membrane TIM23 subunit. Supporting Evidence: PMID:16008839 cytoplasm and mitochondria, Tim50a is strictly nuclear and is enriched in file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 is a single-pass IMM protein with an N-terminal mitochondrial targeting sequence, a transmembrane anchor, and a large IMS-exposed hydrophilic domain that mediates receptor/gating functions.
GO:0005739 mitochondrion	IDA GO_REF:0000052	MARK AS OVER ANNOTATED	Summary: Correct but broad. Canonical TIMM50 is specifically an inner mitochondrial membrane TIM23 complex subunit. Reason: Prefer mitochondrial inner membrane and TIM23 complex annotations over generic mitochondrion. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 is a single-pass IMM protein with an N-terminal mitochondrial targeting sequence, a transmembrane anchor, and a large IMS-exposed hydrophilic domain that mediates receptor/gating functions.
GO:0030150 protein import into mitochondrial matrix	IDA PMID:38828998 Reduced Protein Import via TIM23 SORT Drives Disease Patholo...	ACCEPT	Summary: Correct and core. TIMM50 is the TIM23 presequence receptor/gatekeeper needed for import of transit peptide-containing precursors through the inner membrane toward the matrix or IMM sorting pathway. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 primarily acts on presequence-containing precursor proteins, which constitute a large fraction of the mitochondrial proteome and are imported through the TIM23 pathway for matrix delivery or IMM insertion. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: Correct but broad. Canonical TIMM50 is specifically an inner mitochondrial membrane TIM23 complex subunit. Reason: Prefer mitochondrial inner membrane and TIM23 complex annotations over generic mitochondrion. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 is a single-pass IMM protein with an N-terminal mitochondrial targeting sequence, a transmembrane anchor, and a large IMS-exposed hydrophilic domain that mediates receptor/gating functions.
GO:0005744 TIM23 mitochondrial import inner membrane translocase complex	IDA PMID:30598479 ROMO1 is a constituent of the human presequence translocase ...	ACCEPT	Summary: Correct and core. TIMM50 is a core TIM23 complex subunit that directly coordinates presequence handoff and channel gating. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported. PMID:15044455 complex with human Tim23. Down-regulation of human Tim50 expression by RNA
GO:0005739 mitochondrion	IDA PMID:32848200 Ttm50 facilitates calpain activation by anchoring it to calc...	MARK AS OVER ANNOTATED	Summary: Correct but broad. Canonical TIMM50 is specifically an inner mitochondrial membrane TIM23 complex subunit. Reason: Prefer mitochondrial inner membrane and TIM23 complex annotations over generic mitochondrion. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 is a single-pass IMM protein with an N-terminal mitochondrial targeting sequence, a transmembrane anchor, and a large IMS-exposed hydrophilic domain that mediates receptor/gating functions.
GO:0005783 endoplasmic reticulum	IDA PMID:32848200 Ttm50 facilitates calpain activation by anchoring it to calc...	MARK AS OVER ANNOTATED	Summary: The cited FlyBase-sourced study supports a Drosophila Ttm50 calpain/ER-Golgi calcium-store context, but the human TIMM50 synthesis supports mitochondrial TIM23 import as the established function. Reason: PMID:32848200 studies Drosophila Ttm50, not human TIMM50. Do not treat the noncanonical Ttm50 calpain calcium-store finding as a core human TIMM50 activity or localization without human TIMM50-specific support. Supporting Evidence: PMID:32848200 GluRIIA at the Drosophila neuromuscular junction as a readout, we uncovered that PMID:32848200 stores Golgi and endoplasmic reticulum (ER), and Ttm50 interacts with calpain PMID:32848200 magnitude. Our findings reveal the regulation of calpain activation by Ttm50, file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23.
GO:0005794 Golgi apparatus	IDA PMID:32848200 Ttm50 facilitates calpain activation by anchoring it to calc...	MARK AS OVER ANNOTATED	Summary: The cited FlyBase-sourced study supports a Drosophila Ttm50 calpain/ER-Golgi calcium-store context, but the human TIMM50 synthesis supports mitochondrial TIM23 import as the established function. Reason: PMID:32848200 studies Drosophila Ttm50, not human TIMM50. Do not treat the noncanonical Ttm50 calpain calcium-store finding as a core human TIMM50 activity or localization without human TIMM50-specific support. Supporting Evidence: PMID:32848200 GluRIIA at the Drosophila neuromuscular junction as a readout, we uncovered that PMID:32848200 stores Golgi and endoplasmic reticulum (ER), and Ttm50 interacts with calpain PMID:32848200 magnitude. Our findings reveal the regulation of calpain activation by Ttm50, file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23.
GO:0140608 cysteine-type endopeptidase activator activity	IDA PMID:32848200 Ttm50 facilitates calpain activation by anchoring it to calc...	MARK AS OVER ANNOTATED	Summary: The cited FlyBase-sourced study supports a Drosophila Ttm50 calpain/ER-Golgi calcium-store context, but the human TIMM50 synthesis supports mitochondrial TIM23 import as the established function. Reason: PMID:32848200 studies Drosophila Ttm50, not human TIMM50. Do not treat the noncanonical Ttm50 calpain calcium-store finding as a core human TIMM50 activity or localization without human TIMM50-specific support. Supporting Evidence: PMID:32848200 GluRIIA at the Drosophila neuromuscular junction as a readout, we uncovered that PMID:32848200 stores Golgi and endoplasmic reticulum (ER), and Ttm50 interacts with calpain PMID:32848200 magnitude. Our findings reveal the regulation of calpain activation by Ttm50, file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23.
GO:0001836 release of cytochrome c from mitochondria	IDA PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	KEEP AS NON CORE	Summary: Supported as a downstream consequence of TIMM50 depletion and mitochondrial membrane dysfunction, but it is not the core molecular/cellular role of TIMM50. Reason: TIMM50 loss can accelerate cytochrome c release, but TIMM50 itself is primarily a TIM23 import receptor/gatekeeper. Supporting Evidence: PMID:15044455 accelerating the release of cytochrome c from the mitochondria. Furthermore, file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23.
GO:0004721 phosphoprotein phosphatase activity	IDA PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	MARK AS OVER ANNOTATED	Summary: Human TIMM50 was reported to hydrolyse pNPP and phosphotyrosine and phosphothreonine peptides in vitro (Guo et al. 2004). The full text shows this rests on one assay of GST fusions purified from E. coli, with no catalytic-site mutant and no physiological substrate. TIMM50 lacks the catalytic motif of FCP/SCP phosphatases, and its established role is TIM23 presequence receptor/gatekeeper. Reason: The reported activity is a real in vitro observation, so the annotation is not plainly wrong, but it is weak evidence that phosphatase activity is a function of this protein. (1) The assay used GST fusions purified from E. coli; the controls were GST alone and the N-terminal targeting fragment, and no catalytic-residue mutant was tested, so a co-purifying bacterial phosphatase is not excluded. (2) Activity peaked at pH 4.0-6.0 and declined sharply at basic pH. (3) No physiological substrate was shown; dephosphorylation of Bcl-2 family proteins is offered in the Discussion only as speculation. (4) The CTD-like domain lacks the D-x-D-x-(T/V) catalytic motif of FCP/SCP phosphatases (TIMM50-bioinformatics/RESULTS.md; the T. brucei Tim50 control has it), and the authors note that yeast Tim50 lacks the activity. PAINT blocks the ancestral phosphatase IBD for the whole Tim50 clade, and the PTHR12210 family review judges that block LOSS_SUPPORTED. UniProt likewise says the activity may not be relevant in vivo. Supporting Evidence: PMID:15044455 To test this possibility we expressed N-terminal GST-tagged full-length or truncated human Tim50 in bacteria PMID:15044455 The human Tim50 phosphatase activity displayed a bell-shaped pH profile with an optimum activity around pH 4.0–6.0. Phosphatase activity declined sharply at basic pH PMID:15044455 It is tempting to speculate that in addition to its translocase activity, human Tim50 might also function as a phosphatase for certain mitochondrial proteins PMID:15044455 while yeast Tim50 was reported not to have such an activity file:human/TIMM50/TIMM50-bioinformatics/RESULTS.md \| Q3ZCQ8 \| Homo sapiens \| TIMM50 \| 353 \| none \| file:human/TIMM50/TIMM50-deep-research-falcon.md Therefore, based on available evidence, the primary validated function remains protein import receptor/gating, not a defined metabolic reaction with established substrates.
GO:0005134 interleukin-2 receptor binding	IDA PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	REMOVE	Summary: The cited Tim50 paper and Falcon synthesis do not support an interleukin-2 receptor binding activity for TIMM50; the established molecular role is TIM23 presequence receptor/gating. Reason: The full text of PMID:15044455 (now cached) never mentions interleukin-2 or its receptor. The only receptors it studies are the TRAIL death receptors DR4 and DR5. Human Tim50 was found in a yeast two-hybrid screen with the DR5 death domain, and the isolated C-terminal region bound the DR4/DR5 death domains only when both were overexpressed; the authors could not detect any interaction between the endogenous proteins and attribute the screen result to the two proteins residing in different compartments. So neither IL-2 receptor binding nor death receptor binding is supported. Supporting Evidence: PMID:15044455 Among the isolated cDNA clones, one was able to confer on yeast the ability to grow on Leu-minus medium and strong activation of the GFP reporter gene in the presence of the DR5-death domain bait PMID:15044455 subsequent co-immunoprecipitation assays with extracts from several human cell lines before or after stimulation with TRAIL failed to detect any interactions between the endogenous 40 kDa protein and endogenous DR4 or DR5 file:human/TIMM50/TIMM50-deep-research-falcon.md Therefore, based on available evidence, the primary validated function remains protein import receptor/gating, not a defined metabolic reaction with established substrates. file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23.
GO:0005744 TIM23 mitochondrial import inner membrane translocase complex	IPI PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	ACCEPT	Summary: Correct and core. TIMM50 is a core TIM23 complex subunit that directly coordinates presequence handoff and channel gating. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported. PMID:15044455 complex with human Tim23. Down-regulation of human Tim50 expression by RNA
GO:0004722 protein serine/threonine phosphatase activity	IDA PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	MARK AS OVER ANNOTATED	Summary: Human TIMM50 was reported to hydrolyse pNPP and phosphotyrosine and phosphothreonine peptides in vitro (Guo et al. 2004). The full text shows this rests on one assay of GST fusions purified from E. coli, with no catalytic-site mutant and no physiological substrate. TIMM50 lacks the catalytic motif of FCP/SCP phosphatases, and its established role is TIM23 presequence receptor/gatekeeper. Reason: The reported activity is a real in vitro observation, so the annotation is not plainly wrong, but it is weak evidence that phosphatase activity is a function of this protein. (1) The assay used GST fusions purified from E. coli; the controls were GST alone and the N-terminal targeting fragment, and no catalytic-residue mutant was tested, so a co-purifying bacterial phosphatase is not excluded. (2) Activity peaked at pH 4.0-6.0 and declined sharply at basic pH. (3) No physiological substrate was shown; dephosphorylation of Bcl-2 family proteins is offered in the Discussion only as speculation. (4) The CTD-like domain lacks the D-x-D-x-(T/V) catalytic motif of FCP/SCP phosphatases (TIMM50-bioinformatics/RESULTS.md; the T. brucei Tim50 control has it), and the authors note that yeast Tim50 lacks the activity. PAINT blocks the ancestral phosphatase IBD for the whole Tim50 clade, and the PTHR12210 family review judges that block LOSS_SUPPORTED. UniProt likewise says the activity may not be relevant in vivo. Supporting Evidence: PMID:15044455 To test this possibility we expressed N-terminal GST-tagged full-length or truncated human Tim50 in bacteria PMID:15044455 The human Tim50 phosphatase activity displayed a bell-shaped pH profile with an optimum activity around pH 4.0–6.0. Phosphatase activity declined sharply at basic pH PMID:15044455 It is tempting to speculate that in addition to its translocase activity, human Tim50 might also function as a phosphatase for certain mitochondrial proteins PMID:15044455 while yeast Tim50 was reported not to have such an activity file:human/TIMM50/TIMM50-bioinformatics/RESULTS.md \| Q3ZCQ8 \| Homo sapiens \| TIMM50 \| 353 \| none \| file:human/TIMM50/TIMM50-deep-research-falcon.md Therefore, based on available evidence, the primary validated function remains protein import receptor/gating, not a defined metabolic reaction with established substrates.
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	MARK AS OVER ANNOTATED	Summary: Human TIMM50 was reported to hydrolyse pNPP and phosphotyrosine and phosphothreonine peptides in vitro (Guo et al. 2004). The full text shows this rests on one assay of GST fusions purified from E. coli, with no catalytic-site mutant and no physiological substrate. TIMM50 lacks the catalytic motif of FCP/SCP phosphatases, and its established role is TIM23 presequence receptor/gatekeeper. Reason: The reported activity is a real in vitro observation, so the annotation is not plainly wrong, but it is weak evidence that phosphatase activity is a function of this protein. (1) The assay used GST fusions purified from E. coli; the controls were GST alone and the N-terminal targeting fragment, and no catalytic-residue mutant was tested, so a co-purifying bacterial phosphatase is not excluded. (2) Activity peaked at pH 4.0-6.0 and declined sharply at basic pH. (3) No physiological substrate was shown; dephosphorylation of Bcl-2 family proteins is offered in the Discussion only as speculation. (4) The CTD-like domain lacks the D-x-D-x-(T/V) catalytic motif of FCP/SCP phosphatases (TIMM50-bioinformatics/RESULTS.md; the T. brucei Tim50 control has it), and the authors note that yeast Tim50 lacks the activity. PAINT blocks the ancestral phosphatase IBD for the whole Tim50 clade, and the PTHR12210 family review judges that block LOSS_SUPPORTED. UniProt likewise says the activity may not be relevant in vivo. Supporting Evidence: PMID:15044455 To test this possibility we expressed N-terminal GST-tagged full-length or truncated human Tim50 in bacteria PMID:15044455 The human Tim50 phosphatase activity displayed a bell-shaped pH profile with an optimum activity around pH 4.0–6.0. Phosphatase activity declined sharply at basic pH PMID:15044455 It is tempting to speculate that in addition to its translocase activity, human Tim50 might also function as a phosphatase for certain mitochondrial proteins PMID:15044455 while yeast Tim50 was reported not to have such an activity file:human/TIMM50/TIMM50-bioinformatics/RESULTS.md \| Q3ZCQ8 \| Homo sapiens \| TIMM50 \| 353 \| none \| file:human/TIMM50/TIMM50-deep-research-falcon.md Therefore, based on available evidence, the primary validated function remains protein import receptor/gating, not a defined metabolic reaction with established substrates.
GO:0005515 protein binding	IPI PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	MARK AS OVER ANNOTATED	Summary: Protein binding is true but uninformative for TIMM50. The biologically meaningful interaction context is TIM23 presequence receptor/gating and TIMM23/TIM17 complex membership. Reason: Replace generic interaction capture with TIM23 complex membership and presequence/targeting-sequence binding where supported. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported.
GO:0007006 mitochondrial membrane organization	IMP PMID:15044455 Tim50, a component of the mitochondrial translocator, regula...	KEEP AS NON CORE	Summary: Supported as a cellular consequence of TIMM50 loss causing mitochondrial membrane permeabilization/dysfunction, but it is downstream of the core TIM23 import role. Reason: Keep as non-core because membrane organization phenotypes arise from impaired mitochondrial import/integrity rather than a direct membrane-organizing function. Supporting Evidence: PMID:15044455 indicate that loss of Tim50 in vertebrates causes mitochondrial membrane file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23.
GO:0016607 nuclear speck	IDA Q3ZCQ8-2 PMID:16008839 Tim50a, a nuclear isoform of the mitochondrial Tim50, intera...	KEEP AS NON CORE	Summary: Supported for the Tim50a isoform, but not the core function of the canonical mitochondrial TIMM50 protein. Reason: Track as isoform-specific, non-core nuclear localization; canonical TIMM50 function is mitochondrial TIM23 import. Supporting Evidence: PMID:16008839 cytoplasm and mitochondria, Tim50a is strictly nuclear and is enriched in
GO:0043021 ribonucleoprotein complex binding	IDA Q3ZCQ8-2 PMID:16008839 Tim50a, a nuclear isoform of the mitochondrial Tim50, intera...	KEEP AS NON CORE	Summary: Supported for the nuclear Tim50a isoform, which interacts with snRNP-associated proteins, but this is not the canonical mitochondrial import function. Reason: Keep as an isoform-specific non-core activity distinct from TIM23 presequence import. Supporting Evidence: PMID:16008839 In addition to coilin, Tim50a interacts with snRNPs and PMID:16008839 cytoplasm and mitochondria, Tim50a is strictly nuclear and is enriched in
GO:0140436 mitochondrial signal sequence receptor activity	NAS file:human/TIMM50/TIMM50-deep-research-falcon.md	NEW	Summary: TIMM50 is described as the primary inner-membrane presequence receptor for TIM23 substrates, so mitochondrial signal sequence receptor activity (GO:0140436, the replacement for the obsolete GO:0030943) captures its core molecular function better than generic protein binding. Reason: Existing GOA lacks a specific molecular-function term for TIMM50 presequence/targeting-signal receptor activity. Supporting Evidence: file:human/TIMM50/TIMM50-deep-research-falcon.md Tim50 is widely regarded as the primary presequence receptor at the inner membrane, positioned in the intermembrane space (IMS) to receive precursors emerging from the TOM pore and coordinate their entry into TIM23. file:human/TIMM50/TIMM50-deep-research-falcon.md TIMM50 primarily acts on presequence-containing precursor proteins, which constitute a large fraction of the mitochondrial proteome and are imported through the TIM23 pathway for matrix delivery or IMM insertion. file:human/TIMM50/TIMM50-deep-research-falcon.md This receptor/gating logic is supported by direct presequence-binding mapping and the conclusion that Tim50 binding to Tim23 can induce channel closure when no substrate is being transported.

Gene Description

Existing Annotations Review

Core Functions

TIMM50 is the inner-membrane TIM23 presequence receptor and gatekeeper that captures transit peptide-containing mitochondrial precursors on the intermembrane-space side, coordinates TIM23 channel gating, and supports import into the matrix or IMM sorting pathway.

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