TOMM5

GO Term	Evidence	Action	Reason
GO:0005742 mitochondrial outer membrane translocase complex	IBA GO_REF:0000033	ACCEPT	Summary: Correct phylogenetic inference. TOMM5 is a conserved small Tom subunit of the TOM core complex. Supporting Evidence: file:human/TOMM5/TOMM5-deep-research-falcon.md TOMM5 is a component of the TOM machinery embedded in the mitochondrial outer membrane as part of the detergent-stable TOM core complex
GO:0005741 mitochondrial outer membrane	IEA GO_REF:0000044	ACCEPT	Summary: Correct UniProt-derived localization. Human structural and review evidence place TOMM5 in the mitochondrial outer membrane TOM core.
GO:0005742 mitochondrial outer membrane translocase complex	IEA GO_REF:0000002	ACCEPT	Summary: Correct InterPro-derived complex annotation. TOMM5 is a small subunit of the mitochondrial TOM translocase complex.
GO:0005739 mitochondrion	IDA GO_REF:0000052	MARK AS OVER ANNOTATED	Summary: Correct but less specific than the well-supported mitochondrial outer membrane/TOM complex localization. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005741 mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: Kato and Mihara identified human Tom5 in the outer membrane TOM preprotein translocase complex; this matches the Falcon synthesis of structural evidence.
GO:0045040 protein insertion into mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	MODIFY	Summary: TOMM5 supports TOM organization and biogenesis, but the evidence does not support TOMM5 as an independent insertase for outer membrane proteins. TOM complex assembly is the more precise process annotation. Reason: Replace the insertion term with TOM complex assembly/stability, which is the small Tom5 subunit role supported by structural and ortholog evidence. Proposed replacements: mitochondrial outer membrane translocase complex assembly
GO:0140596 TOM complex	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: Correct and specific. TOMM5 is a detergent-stable TOM core subunit adjacent to TOMM40, TOMM6, TOMM7, and TOMM22.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: High-throughput mitochondrial proteome data support mitochondrial localization, but the term is too general for a TOM outer membrane core subunit. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5205661	ACCEPT	Summary: Reactome places TOMM5 at the mitochondrial outer membrane in TOM/PINK1 pathway context. This agrees with the TOM core localization.
GO:0070585 protein localization to mitochondrion	IC PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	KEEP AS NON CORE	Summary: Correct as a broad process annotation for a TOM complex subunit, but TOMM5's more specific role is structural support of TOM core assembly and organization. Reason: Broad process term; the synthesized core function emphasizes TOM complex assembly/stability.
GO:0005742 mitochondrial outer membrane translocase complex	IDA PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: Direct evidence from Kato and Mihara supports human TOMM5 membership in the mitochondrial outer membrane translocase complex. A cryo-EM structure of the endogenous TOM-VDAC array (PMID:40080546; PDB 9EIH/9EII/9EIJ) independently resolves TOM5 within the assembled TOM core complex. Supporting Evidence: PMID:40080546 TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and

Deep Research

Falcon

(TOMM5-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 42 citations 2026-05-11T11:14:28.477844

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.

Research report: Human TOMM5 (UniProt Q8N4H5; Tom5 family) functional annotation

0) Identity verification (critical disambiguation)

The gene TOMM5 (synonyms TOM5, C9orf105) encodes the human homolog of the TOM-complex small subunit Tom5, a single-pass α-helical protein that is part of the mitochondrial translocase of the outer membrane (TOM) complex (pitt2021abiochemicaland pages 1-3, pitt2021abiochemicaland pages 6-9). The literature retrieved here consistently uses “Tom5/TOMM5” to denote this TOM-complex subunit and does not indicate an alternative human gene/protein with the same symbol in this context (pitt2021abiochemicaland pages 1-3).

1) Key concepts and definitions (current understanding)

1.1 The TOM complex and mitochondrial protein import

Mammalian mitochondria import the vast majority of their proteins from the cytosol; reviews typically cite ~1,000–1,500 mitochondrial proteins, with import across the outer membrane occurring primarily through the TOM complex (pitt2021abiochemicaland pages 16-17, pitt2021abiochemicaland pages 6-9). The TOM complex is organized around the β‑barrel channel TOMM40/Tom40, with additional receptor and small accessory subunits that contribute to recognition, translocation, and complex organization (pitt2021abiochemicaland pages 1-3, pitt2021abiochemicaland pages 6-9).

1.2 What TOMM5 is (and is not)

TOMM5 is not an enzyme and has no known catalytic reaction or substrate specificity in the enzyme/transporter sense. Rather, TOMM5 is best understood as a structural/regulatory accessory subunit of a large membrane translocase, contributing to the assembly, stability, and/or mechanistic routing properties of the TOM pore (tucker2019cryoemstructureof pages 1-3, pitt2021abiochemicaland pages 6-9).

2) Molecular function of TOMM5 in the TOM complex

2.1 Core biochemical role (inferred from structure + ortholog experiments)

Across species, Tom5-family proteins are described as small TOM subunits that directly associate with the Tom40 β‑barrel and are proposed to support: (i) TOM complex stability/organization, (ii) precursor handling/transfer, and (iii) biogenesis/assembly of TOM components (tucker2019cryoemstructureof pages 1-3, becker2010assemblyofthe pages 1-2, bausewein2020thestructureof pages 5-8).

A key mechanistic idea emphasized in structural reviews is that Tom5 sits at a peripheral region of the TOM dimer and is positioned to participate in routing or recruitment events for particular classes of imported precursors (araiso2022structuraloverviewof pages 1-3). In particular, Araiso & Endo summarize cryo‑EM-derived models in which the N‑terminal segment of Tom40 traverses the channel and interacts with Tom5 at the periphery of the TOM dimer; this site is discussed as a location where downstream components for presequence‑lacking precursors can be recruited (araiso2022structuraloverviewof pages 1-3).

2.2 Role in TOM biogenesis/assembly (strongest direct experimental evidence is fungal/yeast)

The most direct causal evidence for a Tom5-family protein in TOM assembly comes from yeast: Becker et al. identified a Tom40 assembly intermediate at the SAM complex and concluded that Tom5 associates with the Tom40 precursor at the SAM complex in a later stage that promotes Tom40 assembly; Tom5 thereby helps progress Tom40 from early SAM-associated intermediates toward mature TOM complexes (becker2010assemblyofthe pages 1-2). While this is not human TOMM5 per se, it is widely used as the mechanistic basis for inferring a conserved Tom5 contribution to TOM core biogenesis (becker2010assemblyofthe pages 1-2, pitt2021abiochemicaland pages 6-9).

3) Subcellular localization and topology (human-specific structural evidence)

3.1 Localization

TOMM5 is a component of the TOM machinery embedded in the mitochondrial outer membrane as part of the detergent-stable TOM core complex (pitt2021abiochemicaland pages 6-9, guan2021structuralinsightsinto media bb38bae5).

3.2 Topology and position within the human TOM core

Human cryo‑EM structures of the TOM core complex resolve Tom5 (TOMM5) as a single-pass α‑helical subunit that surrounds the Tom40 β‑barrel together with Tom6 and Tom7 (pitt2021abiochemicaland pages 6-9). In the human TOM core complex structure presented by Guan et al., Tom5 is located on the periphery of each Tom40 barrel (rather than at the Tom22-bridged central interface), consistent with a peripheral accessory role (guan2021structuralinsightsinto media bb38bae5, guan2021structuralinsightsinto media 07568b50).

4) Interaction partners and complex membership

4.1 TOM core membership and direct contacts

Structural and review evidence places TOMM5 as a β‑barrel-associated TOM core subunit that directly contacts TOMM40/Tom40, and resides adjacent to Tom6, Tom7, and Tom22 in the assembled complex (pitt2021abiochemicaland pages 6-9, pitt2021abiochemicaland pages 3-6). The TOM core is observed in multiple oligomeric states (dimeric/tetrameric/trimeric forms) that all retain Tom5 as part of the assembly (pitt2021abiochemicaland pages 11-12).

4.2 Oligomeric state statistics (structural)

A review synthesis of cryo‑EM findings reports TOM core oligomers that include:
* a dimeric core containing a dimer of Tom40 with Tom5, Tom6, Tom7, and Tom22;
* a tetrameric arrangement (dimer of dimers) with two copies each of Tom6, Tom22, and Tom5 at the dimer–dimer interface; and
* a trimeric TOM containing three copies of Tom40, Tom5, Tom6, Tom7, Tom22 (pitt2021abiochemicaland pages 11-12).

5) Recent developments and latest research (priority 2023–2024)

5.1 2023: TOMM5 as a mitochondrial microprotein in a large translocase

A 2023 review focused on mitochondrial microproteins explicitly catalogs TOMM5 as a 51‑amino‑acid TOM component and describes Tom5/TOMM5 (with TOMM6 and TOMM7) as associating with TOMM40 and regulating stability of the import channel; the review also contextualizes the TOM complex as an ~440 kDa system (kamradt2023mitochondrialmicroproteinscritical pages 1-4). Although the excerpted text is review-level (not a new primary perturbation study), it represents current (2023) consensus framing of TOMM5’s role as a very small structural regulator embedded in a major import machine (kamradt2023mitochondrialmicroproteinscritical pages 1-4).

5.2 2024: Structure/dynamics-focused TOM reviews reinforce TOMM5’s role as a small core subunit

A 2024 Biochemical Society Transactions review on TOM structure/dynamics lists Tom5 among the holo-complex subunits and emphasizes the structural context of a two‑pore Tom40 architecture revealed by cryo‑EM; it additionally notes that Tom5 shows relatively low sequence identity across fungi, consistent with evolutionary flexibility outside small conserved motifs (nussberger2024newinsightsinto pages 2-4). A complementary structure-centric synthesis also frames Tom5 among the “low molecular weight” TOM subunits implicated in assembly/stability and possible precursor handover at the cytosolic face (bausewein2020thestructureof pages 5-8).

6) Disease relevance, phenotypes, and real-world implementations

6.1 Human disease genetics: limited TOMM5-specific evidence in retrieved primary literature

In the retrieved sources, there is no well-established monogenic human disease directly attributed to TOMM5 variants, and human TOMM5-specific functional perturbation datasets were not prominent in the accessible full texts (pitt2021abiochemicaland pages 16-17, pitt2021abiochemicaland pages 3-6). Database-level disease-target associations exist (e.g., Open Targets lists several diseases with low overall association scores and evidence largely driven by limited literature and functional genomics screens), but these should be treated as hypothesis-generating rather than confirmatory (OpenTargets Search: -TOMM5).

6.2 Strongest organismal phenotype evidence: Tomm5−/− mice

A dedicated mouse knockout pathology study reported that Tomm5−/− mice develop a striking lung-restricted phenotype resembling human cryptogenic organizing pneumonia (COP), with patchy intra-alveolar organizing lesions that evolve into fibrogenic buds containing extracellular matrix components and α‑SMA-positive myofibroblasts; the authors propose impaired mitochondrial function/import during neonatal transition to air and oxidative stress as plausible contributing mechanisms (vogel2013cryptogenicorganizingpneumonia pages 1-2, vogel2013cryptogenicorganizingpneumonia pages 5-7). This provides important in vivo evidence that Tomm5 can be physiologically important, though it does not by itself establish a direct human TOMM5 disease mechanism (vogel2013cryptogenicorganizingpneumonia pages 5-7).

6.3 Applications and implementations in research/biomedicine

Structure-enabled mechanistic modeling: Human cryo‑EM structures (and their review syntheses) are actively used to infer how accessory subunits such as Tom5 position around Tom40 and may influence routing and complex dynamics (guan2021structuralinsightsinto media bb38bae5, araiso2022structuraloverviewof pages 1-3).
Mitochondrial targeting tools: A TOM review notes that human Tom5 has been used as a mitochondrial-targeting fusion in a cancer-cell context (e.g., to deliver p53 to mitochondria), illustrating use of TOMM5-derived sequences as experimental targeting elements; however, this is not yet a validated therapeutic approach (pitt2021abiochemicaland pages 16-17).

7) Expert synthesis and interpretation (authoritative viewpoints)

Confidence-high statements (human structural context): TOMM5 is a small α‑helical TOM core subunit that directly contacts Tom40 and is positioned peripherally in human TOM core cryo‑EM reconstructions (guan2021structuralinsightsinto media bb38bae5, pitt2021abiochemicaland pages 6-9).
Moderate-confidence mechanistic role (cross-species inference): Tom5-family proteins likely contribute to TOM assembly/biogenesis and stability, supported strongly by yeast SAM-associated assembly intermediates and widely extrapolated to metazoans (becker2010assemblyofthe pages 1-2, pitt2021abiochemicaland pages 6-9).
Open questions emphasized by experts: Reviews explicitly state that functional knowledge for Tom5/TOMM5 in humans remains limited compared with other subunits; some yeast-specific mechanistic features (Tom40 regions implicated in Tom5 interactions) may not be conserved in human Tom40, implying that the exact human mechanism could differ (pitt2021abiochemicaland pages 16-17).

8) Key statistics and data points (from recent/authoritative sources)

TOMM5 is described as ~51 aa in a 2023 mitochondrial microprotein review (kamradt2023mitochondrialmicroproteinscritical pages 1-4).
TOM (reviewed) is an ~440 kDa complex (kamradt2023mitochondrialmicroproteinscritical pages 1-4).
TOM core oligomeric states reported from cryo‑EM include dimeric/tetrameric/trimeric assemblies containing Tom5, with two copies of Tom5 at the tetramer interface (review synthesis) (pitt2021abiochemicaland pages 11-12).

9) Summary table of evidence

The following table consolidates high-confidence annotation statements, clearly separating human-structure-based evidence from inferences and remaining gaps.

Annotation topic	Key points	Best supporting sources
Protein identity	• Human gene/protein verified as TOMM5 / Tom5, UniProt Q8N4H5 • Small Tom5-family subunit of the mitochondrial TOM (translocase of outer membrane) complex • Reviewed as one of the canonical TOM components in human mitochondria	Pitt & Buchanan, 2021, https://doi.org/10.3390/cells10051164 (pitt2021abiochemicaland pages 1-3, pitt2021abiochemicaland pages 3-6); Lionaki et al., 2023, https://doi.org/10.1002/bies.202200160
Subcellular localization / topology	• Localized to the mitochondrial outer membrane within the TOM core complex • Single-pass α-helical membrane protein; one of the small TOM subunits • In human cryo-EM structures, Tom5 lies on the periphery of each Tom40 barrel, opposite the Tom22-bridged central interface	Guan et al., 2021, https://doi.org/10.1038/s41421-021-00252-7 (guan2021structuralinsightsinto media bb38bae5, guan2021structuralinsightsinto media 07568b50); Wang et al., 2020, https://doi.org/10.1038/s41421-020-00198-2; Araiso & Endo, 2022, https://doi.org/10.2142/biophysico.bppb-v19.0022 (araiso2022structuraloverviewof pages 1-3)
Molecular function	• Not an enzyme; acts as a structural/regulatory accessory subunit of the TOM import channel • Proposed roles include precursor transfer, binding-site formation, and assembly/stability support for TOM • Functional assignment in humans remains partly inferred from structure and fungal homologs	Tucker & Park, 2019, https://doi.org/10.1038/s41594-019-0339-2 (tucker2019cryoemstructureof pages 1-3); Pitt & Buchanan, 2021, https://doi.org/10.3390/cells10051164 (pitt2021abiochemicaland pages 6-9, pitt2021abiochemicaland pages 16-17)
Complex membership / interactions	• Member of the detergent-stable TOM core with Tom40, Tom22, Tom6, Tom7 • Directly contacts Tom40; positioned near Tom22/Tom6/Tom7 in dimeric and higher-order assemblies • Human TOM cores resolved as dimers, with tetrameric/higher-order states also observed	Pitt & Buchanan, 2021, https://doi.org/10.3390/cells10051164 (pitt2021abiochemicaland pages 3-6, pitt2021abiochemicaland pages 11-12, pitt2021abiochemicaland pages 6-9); Guan et al., 2021, https://doi.org/10.1038/s41421-021-00252-7; Wang et al., 2020, https://doi.org/10.1038/s41421-020-00198-2
Role in import mechanism	• TOM is the main entry gate for most nuclear-encoded mitochondrial proteins; Tom5 contributes as an auxiliary subunit rather than a receptor with a known substrate specificity • Structural review places Tom5 near the Tom40 N-terminal segment and a peripheral route implicated in recruiting downstream factors for presequence-lacking precursors • Detailed human-specific mechanistic proof remains limited	Araiso & Endo, 2022, https://doi.org/10.2142/biophysico.bppb-v19.0022 (araiso2022structuraloverviewof pages 1-3); Pitt & Buchanan, 2021, https://doi.org/10.3390/cells10051164 (pitt2021abiochemicaland pages 16-17)
Role in TOM biogenesis / assembly	• Best direct evidence comes from yeast/fungal ortholog studies: Tom5 promotes a later SAM-associated Tom40 assembly stage • Supports formation of stable intermediates for integration of newly synthesized TOM components • Human role is widely inferred to involve assembly and maintenance of TOM, but dedicated endogenous TOMM5 perturbation data are scarce	Becker et al., 2010, https://doi.org/10.1091/mbc.e10-06-0518 (becker2010assemblyofthe pages 1-2); Pitt & Buchanan, 2021, https://doi.org/10.3390/cells10051164 (pitt2021abiochemicaland pages 6-9, pitt2021abiochemicaland pages 16-17)
Recent 2023–2024 developments	• 2023 review highlights TOMM5 as a 51-aa mitochondrial microprotein embedded in a large import machine • 2024 reviews emphasize evolutionary conservation of the TOM architecture and new structure/dynamics insights, reinforcing Tom5 as a small regulatory/core-surrounding subunit • Recent work refines complex architecture and dynamics more than TOMM5-specific biochemistry	Kamradt & Makarewich, 2023, https://doi.org/10.1152/ajpcell.00189.2023; Lionaki et al., 2023, https://doi.org/10.1002/bies.202200160; Nussberger et al., 2024, https://doi.org/10.1042/bst20231236; Özdemir & Dennerlein, 2024, https://doi.org/10.1515/hsz-2024-0043
Disease / phenotype links	• No well-established monogenic human TOMM5 disease is supported by the retrieved primary literature • Broader TOM dysfunction is linked to neurodegeneration, cardiovascular disease, mitophagy defects, and cancer biology, but this is usually driven by other TOM subunits • Database-level disease associations for TOMM5 exist but are low-confidence / indirect and should be interpreted cautiously	Heinemeyer et al., 2019, https://doi.org/10.1089/dna.2018.4292; Zhao & Zou, 2021, https://doi.org/10.3389/fcvm.2021.749756; Open Targets (accessed via tool output) (OpenTargets Search: -TOMM5)
Model-organism phenotype evidence	• A mouse knockout report described cryptogenic organizing pneumonia in Tomm5−/− mice, indicating organism-level importance • This phenotype is informative but does not yet define the precise molecular lesion in human cells • Separate TOM-complex small-subunit disease precedent exists for TOMM7, underscoring plausibility of TOM small-subunit pathology	Vogel et al., 2013, https://doi.org/10.1177/0300985812450723; Young et al., 2023, https://doi.org/10.1016/j.xhgg.2022.100148
Knowledge gaps / confidence limits	• Human endogenous TOMM5 loss-of-function studies are very limited • No clear human substrate specificity, catalytic activity, or direct disease-causing variants established • Many functional claims are extrapolated from fungal orthologs and from TOM-complex structural context rather than TOMM5-specific perturbation experiments	Pitt & Buchanan, 2021, https://doi.org/10.3390/cells10051164 (pitt2021abiochemicaland pages 16-17, pitt2021abiochemicaland pages 3-6); Nussberger et al., 2024, https://doi.org/10.1042/bst20231236

Table: This table summarizes the strongest currently available evidence for human TOMM5 functional annotation, emphasizing what is directly supported in humans versus what is inferred from TOM-complex structure or fungal ortholog studies. It is useful for distinguishing high-confidence facts from remaining knowledge gaps.

10) Conclusions (functional annotation statement)

Human TOMM5 (Q8N4H5) encodes a very small, single-pass α‑helical subunit of the mitochondrial TOM protein import machinery. The highest-confidence human evidence is structural: TOMM5 is a peripheral β‑barrel-associated component of the TOM core that directly contacts TOMM40/Tom40 and sits adjacent to Tom6/Tom7/Tom22 in the assembled pore complex (guan2021structuralinsightsinto media bb38bae5, pitt2021abiochemicaland pages 6-9). Mechanistically, TOMM5 is best annotated as an accessory structural/regulatory subunit that supports TOM complex organization and likely assists biogenesis/assembly (strongest causal evidence from yeast) rather than acting as a receptor with defined substrate specificity (becker2010assemblyofthe pages 1-2, pitt2021abiochemicaland pages 16-17). TOMM5-specific human disease genetics remain underdeveloped in the retrieved literature, but a Tomm5 knockout mouse phenotype indicates potential organism-level importance and motivates deeper human functional and genetic studies (vogel2013cryptogenicorganizingpneumonia pages 5-7).

URLs (most central sources)

Guan et al. 2021 (Cell Discovery; human TOM core structures): https://doi.org/10.1038/s41421-021-00252-7 (guan2021structuralinsightsinto media bb38bae5, guan2021structuralinsightsinto media 07568b50)
Wang et al. 2020 (Cell Discovery; atomic human TOM core): https://doi.org/10.1038/s41421-020-00198-2
Pitt & Buchanan 2021 (Cells; TOM complex interactions/disease context): https://doi.org/10.3390/cells10051164 (pitt2021abiochemicaland pages 6-9, pitt2021abiochemicaland pages 16-17)
Kamradt & Makarewich 2023 (AJP-Cell; mitochondrial microproteins): https://doi.org/10.1152/ajpcell.00189.2023 (kamradt2023mitochondrialmicroproteinscritical pages 1-4)
Nussberger et al. 2024 (Biochem Soc Trans; TOM structure/dynamics): https://doi.org/10.1042/bst20231236 (nussberger2024newinsightsinto pages 2-4)
Araiso & Endo 2022 (Biophysics and Physicobiology; TOM structural overview): https://doi.org/10.2142/biophysico.bppb-v19.0022 (araiso2022structuraloverviewof pages 1-3)
Becker et al. 2010 (MBoC; Tom5 in Tom40 assembly, yeast): https://doi.org/10.1091/mbc.e10-06-0518 (becker2010assemblyofthe pages 1-2)
Vogel et al. 2013 (Vet Pathol; Tomm5−/− mouse COP-like phenotype): https://doi.org/10.1177/0300985812450723 (vogel2013cryptogenicorganizingpneumonia pages 5-7, vogel2013cryptogenicorganizingpneumonia pages 1-2)

References

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(OpenTargets Search: -TOMM5): Open Targets Query (-TOMM5, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
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Citations

pitt2021abiochemicaland pages 1-3
araiso2022structuraloverviewof pages 1-3
becker2010assemblyofthe pages 1-2
pitt2021abiochemicaland pages 6-9
pitt2021abiochemicaland pages 11-12
kamradt2023mitochondrialmicroproteinscritical pages 1-4
nussberger2024newinsightsinto pages 2-4
bausewein2020thestructureof pages 5-8
vogel2013cryptogenicorganizingpneumonia pages 5-7
pitt2021abiochemicaland pages 16-17
tucker2019cryoemstructureof pages 1-3
pitt2021abiochemicaland pages 3-6
vogel2013cryptogenicorganizingpneumonia pages 1-2
https://doi.org/10.3390/cells10051164
https://doi.org/10.1002/bies.202200160
https://doi.org/10.1038/s41421-021-00252-7
https://doi.org/10.1038/s41421-020-00198-2;
https://doi.org/10.2142/biophysico.bppb-v19.0022
https://doi.org/10.1038/s41594-019-0339-2
https://doi.org/10.1038/s41421-021-00252-7;
https://doi.org/10.1038/s41421-020-00198-2
https://doi.org/10.1091/mbc.e10-06-0518
https://doi.org/10.1152/ajpcell.00189.2023;
https://doi.org/10.1002/bies.202200160;
https://doi.org/10.1042/bst20231236;
https://doi.org/10.1515/hsz-2024-0043
https://doi.org/10.1089/dna.2018.4292;
https://doi.org/10.3389/fcvm.2021.749756;
https://doi.org/10.1177/0300985812450723;
https://doi.org/10.1016/j.xhgg.2022.100148
https://doi.org/10.1042/bst20231236
https://doi.org/10.1152/ajpcell.00189.2023
https://doi.org/10.1177/0300985812450723
https://doi.org/10.3390/cells10051164,
https://doi.org/10.1038/s41594-019-0339-2,
https://doi.org/10.1091/mbc.e10-06-0518,
https://doi.org/10.1515/hsz-2020-0104,
https://doi.org/10.2142/biophysico.bppb-v19.0022,
https://doi.org/10.1038/s41421-021-00252-7,
https://doi.org/10.1152/ajpcell.00189.2023,
https://doi.org/10.1042/bst20231236,
https://doi.org/10.1177/0300985812450723,

📄 View Raw YAML

id: Q8N4H5
gene_symbol: TOMM5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TOMM5 is a very small single-pass mitochondrial outer membrane subunit of the
  TOM translocase core. It is a structural/regulatory accessory component, not
  an enzyme or independent receptor, and supports TOM core organization,
  stability, and biogenesis around TOMM40.
alternative_products:
- name: '1'
  id: Q8N4H5-1
- name: '2'
  id: Q8N4H5-2
  sequence_note: VSP_046982
- name: '3'
  id: Q8N4H5-3
  sequence_note: VSP_046983
existing_annotations:
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Correct phylogenetic inference. TOMM5 is a conserved small Tom subunit of
      the TOM core complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TOMM5/TOMM5-deep-research-falcon.md
      supporting_text: "TOMM5 is a component of the TOM machinery embedded in the **mitochondrial outer membrane** as part of the detergent-stable TOM **core complex**"
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Correct UniProt-derived localization. Human structural and review evidence
      place TOMM5 in the mitochondrial outer membrane TOM core.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Correct InterPro-derived complex annotation. TOMM5 is a small subunit of
      the mitochondrial TOM translocase complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      Correct but less specific than the well-supported mitochondrial outer
      membrane/TOM complex localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: >-
      Kato and Mihara identified human Tom5 in the outer membrane TOM
      preprotein translocase complex; this matches the Falcon synthesis of
      structural evidence.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0045040
    label: protein insertion into mitochondrial outer membrane
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: >-
      TOMM5 supports TOM organization and biogenesis, but the evidence does not
      support TOMM5 as an independent insertase for outer membrane proteins.
      TOM complex assembly is the more precise process annotation.
    action: MODIFY
    reason: >-
      Replace the insertion term with TOM complex assembly/stability, which is
      the small Tom5 subunit role supported by structural and ortholog evidence.
    proposed_replacement_terms:
    - id: GO:0070096
      label: mitochondrial outer membrane translocase complex assembly
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0140596
    label: TOM complex
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: >-
      Correct and specific. TOMM5 is a detergent-stable TOM core subunit
      adjacent to TOMM40, TOMM6, TOMM7, and TOMM22.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: >-
      High-throughput mitochondrial proteome data support mitochondrial
      localization, but the term is too general for a TOM outer membrane core
      subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5205661
  review:
    summary: >-
      Reactome places TOMM5 at the mitochondrial outer membrane in TOM/PINK1
      pathway context. This agrees with the TOM core localization.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: IC
  original_reference_id: PMID:18331822
  review:
    summary: >-
      Correct as a broad process annotation for a TOM complex subunit, but
      TOMM5's more specific role is structural support of TOM core assembly and
      organization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad process term; the synthesized core function emphasizes TOM complex
      assembly/stability.
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IDA
  original_reference_id: PMID:18331822
  review:
    summary: >-
      Direct evidence from Kato and Mihara supports human TOMM5 membership in
      the mitochondrial outer membrane translocase complex. A cryo-EM structure
      of the endogenous TOM-VDAC array (PMID:40080546; PDB 9EIH/9EII/9EIJ)
      independently resolves TOM5 within the assembled TOM core complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM5/TOMM5-deep-research-falcon.md
    - PMID:40080546
    supported_by:
    - reference_id: PMID:40080546
      supporting_text: "TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings:
  - statement: InterPro2GO assigns TOM complex membership based on the Tom5 family
      signature.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: PAINT/IBA phylogenetic propagation supports TOM complex membership
      for TOMM5 across Tom5 orthologs.
- 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:
  - statement: UniProt subcellular location vocabulary maps TOMM5 to the mitochondrial
      outer membrane.
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings:
  - statement: Curated immunofluorescence data place TOMM5 in mitochondria.
- id: PMID:18331822
  title: Identification of Tom5 and Tom6 in the preprotein translocase complex of
    human mitochondrial outer membrane.
  findings:
  - statement: Human Tom5 was immuno-isolated as part of the human TOM preprotein
      translocase complex from HeLa cells.
    supporting_text: We immuno-isolated the TOM complex from HeLa cells expressing
      hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together
      with the other components including Tom7.
  - statement: Tom5 is associated with Tom40 in the human TOM complex.
    supporting_text: These small Tom proteins are associated with Tom40 in the TOM
      complex.
  - statement: Knockdown of Tom7, but not Tom5 or Tom6, strongly compromises TOM
      complex stability; double knockdown of any small-Tom combination affects
      preprotein import, supporting a structural-integrity role for the small TOM
      subunits.
    supporting_text: Knockdown of Tom7, but not Tom5 and Tom6, strongly compromised
      stability of the TOM complex.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: Quantitative MS-based human mitochondrial proteome supports mitochondrial
      localization of TOMM5.
    supporting_text: Quantitative high-confidence human mitochondrial proteome and
      its dynamics in cellular context.
- id: Reactome:R-HSA-5205661
  title: Pink1 is recruited from the cytoplasm to the mitochondria
  findings:
  - statement: Reactome places TOMM5 at the mitochondrial outer membrane as a TOM
      complex subunit in the PINK1 recruitment pathway.
- id: PMID:40080546
  title: Structure of human PINK1 at a mitochondrial TOM-VDAC array.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Cryo-EM structure (PDB 9EIH/9EII/9EIJ) of dimeric human PINK1 stabilized at
      an endogenous TOM-VDAC array; TOMM5 appears incidentally as a TOM core
      subunit that, with TOM20, facilitates the symmetric two-TOM/VDAC2
      arrangement and binds the PINK1 kinase C-lobes.
  findings:
  - statement: >-
      In the endogenous TOM-VDAC array structure, TOM5 (TOMM5) is part of the TOM
      core complex and facilitates the symmetric arrangement of two TOM core
      complexes around a central VDAC2 dimer.
    supporting_text: "TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and"
- id: file:human/TOMM5/TOMM5-deep-research-falcon.md
  title: Falcon deep research report for human TOMM5
  findings:
  - statement: TOMM5 is a single-pass α-helical small Tom subunit of the mitochondrial
      TOM translocase, not an independent enzyme or transporter.
    supporting_text: "encodes the human homolog of the TOM-complex small subunit\
      \ **Tom5**, a **single-pass α-helical** protein that is part of the mitochondrial\
      \ **translocase of the outer membrane (TOM) complex**"
  - statement: TOMM5 is an accessory structural/regulatory subunit supporting TOM
      complex stability, organization, and biogenesis around Tom40.
    supporting_text: "TOMM5 is best understood as a **structural/regulatory accessory\
      \ subunit** of a large membrane translocase, contributing to the assembly,\
      \ stability, and/or mechanistic routing properties of the TOM pore"
  - statement: In the human TOM core structure, Tom5 is single-pass α-helical and
      sits at the periphery of each Tom40 barrel together with Tom6 and Tom7.
    supporting_text: "Tom5 (TOMM5) as a **single-pass α‑helical** subunit that\
      \ **surrounds** the Tom40 β‑barrel together with Tom6 and Tom7"
  - statement: The N-terminal segment of Tom40 traverses the channel and interacts
      with Tom5 at the periphery of the TOM dimer, a site implicated in recruitment
      of factors for presequence-lacking precursors.
    supporting_text: "the **N‑terminal segment of Tom40** traverses the channel\
      \ and **interacts with Tom5** at the **periphery** of the TOM dimer"
  - statement: Yeast ortholog evidence indicates Tom5 associates with the Tom40
      precursor at the SAM complex during late TOM assembly, supporting a conserved
      role in TOM core biogenesis.
    supporting_text: "**Tom5 associates with the Tom40 precursor at the SAM complex**\
      \ in a later stage that promotes Tom40 assembly"
core_functions:
- description: >-
    TOMM5 is a structural/regulatory small Tom subunit that contributes to the
    TOM core translocase by stabilizing TOMM40-containing assemblies and likely
    assisting TOM biogenesis.
  supported_by:
  - reference_id: file:human/TOMM5/TOMM5-deep-research-falcon.md
    supporting_text: "TOMM5 is **not an enzyme** and has **no known catalytic reaction or substrate specificity** in the enzyme/transporter sense."
  - reference_id: file:human/TOMM5/TOMM5-deep-research-falcon.md
    supporting_text: "TOMM5 is a component of the TOM machinery embedded in the **mitochondrial outer membrane** as part of the detergent-stable TOM **core complex**"
  - reference_id: file:human/TOMM5/TOMM5-deep-research-falcon.md
    supporting_text: "Mechanistically, TOMM5 is best annotated as an **accessory structural/regulatory subunit** that supports TOM complex organization and likely assists biogenesis/assembly"
  contributes_to_molecular_function:
    id: GO:0008320
    label: protein transmembrane transporter activity
  directly_involved_in:
  - id: GO:0070096
    label: mitochondrial outer membrane translocase complex assembly
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  in_complex:
    id: GO:0140596
    label: TOM complex
proposed_new_terms: []
suggested_questions:
- question: >-
    Which Tom5 contacts in the human TOM core are essential for TOMM40 assembly
    versus precursor routing?
  experts: []
- question: >-
    How much of TOMM5 function in human cells can be separated from conserved
    yeast Tom5 roles in late Tom40 assembly at SAM?
  experts: []
suggested_experiments:
- hypothesis: >-
    TOMM5 promotes stable TOM core biogenesis by contacting TOMM40 during or
    after TOMM40 assembly.
  description: >-
    Use endogenous TOMM5 depletion/rescue with structure-guided mutants and
    measure TOMM40 assembly intermediates, mature TOM complex abundance, and
    import of representative mitochondrial precursor classes.
  experiment_type: endogenous rescue and mitochondrial import assay

Gene Description

Existing Annotations Review

Core Functions

TOMM5 is a structural/regulatory small Tom subunit that contributes to the TOM core translocase by stabilizing TOMM40-containing assemblies and likely assisting TOM biogenesis.