TOM22

UniProt ID: P49334
Organism: Saccharomyces cerevisiae
Review Status: IN PROGRESS
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Gene Description

Yeast TOM22 (Mom22/Mas17/Mas22) encodes Tom22, a single-pass type II outer mitochondrial membrane protein that serves as the central receptor and organizing scaffold of the translocase of the outer mitochondrial membrane (TOM) complex. Together with Tom20 and Tom70, it forms the transit peptide receptor at the outer membrane surface, recognizes cytosolically synthesized mitochondrial preproteins, and transfers them toward the Tom40 translocation pore. Its cytosolic domain docks Tom20 and Tom70 to the general import pore (GIP) complex, its intermembrane space domain provides a trans binding site for presequences, and its transmembrane anchor is required to stabilize the higher-order TOM machinery and to control Tom40 channel gating. Tom22 also contributes to Tom40 biogenesis and Tom40 Ξ²-barrel insertion into the outer membrane through TOM–SAM handoff.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005742 mitochondrial outer membrane translocase complex
IBA
GO_REF:0000033 		ACCEPT
Summary: Correct. Tom22 is a core receptor/scaffold subunit of the TOM (translocase of outer mitochondrial membrane) complex.
Supporting Evidence:
PMID:9774667
The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
PMID:9774667
The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
GO:0030150 protein import into mitochondrial matrix
IBA
GO_REF:0000033 		ACCEPT
Summary: Correct as a TOM-entry step for matrix-destined mitochondrial preproteins. Tom22 is a receptor/scaffold that recognizes preproteins and transfers them toward the Tom40 pore for downstream TIM23/PAM-mediated matrix import. Tom22 also participates in non-matrix import routes, so this BP captures one of several TOM-mediated pathways.
Supporting Evidence:
PMID:10519552
The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
PMID:10519552
Here we report the unexpected observation that a yeast strain can survive without Tom22, although it is strongly reduced in growth and the import of mitochondrial proteins.
GO:0008320 protein transmembrane transporter activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Accepted as a contribution to TOM complex protein transmembrane transporter activity. Tom22 is the central receptor/scaffold that recognizes preproteins and transfers them to the Tom40 pore; the `contributes_to` qualifier is the appropriate semantic for a complex subunit that does not independently carry out transmembrane transport but is required for the activity of the complex that does.
Reason: Upstream go-annotation issue #6466 raised the concern that "tom40 is the channel, we don't know the MF of tom22" and suggested removing this IBA propagation. The annotation is retained because (a) it carries the `contributes_to` qualifier, which by GO semantics indicates a subunit-level contribution to a complex-level activity (not a claim that Tom22 independently translocates substrate); (b) the same propagation is annotated by SGD as an experimental IMP (PMID:10519552) β€” Tom22 is required for tight control of channel gating and the higher-order organisation that sustains import; and (c) the parallel human TOMM22 review (genes/human/TOMM22/TOMM22-ai-review.yaml) reaches the same conclusion. Tom40 should retain `enables GO:0008320` while Tom22 retains `contributes_to GO:0008320`.
Supporting Evidence:
PMID:10519552
In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating.
PMID:10519552
Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery.
file:human/TOMM22/TOMM22-deep-research-falcon.md
TOMM22 functions as a **major preprotein-binding site** and **organizational scaffold** for the TOM complex, helping recognize mitochondrial precursor proteins and transfer them toward the **Tom40 import pore**.
GO:0005741 mitochondrial outer membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Correct. Tom22 is a single-pass type II mitochondrial outer membrane protein.
Supporting Evidence:
PMID:9774667
The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
GO:0005742 mitochondrial outer membrane translocase complex
IEA
GO_REF:0000002 		ACCEPT
Summary: Correct. Tom22 is a core subunit of the TOM/translocase complex.
Supporting Evidence:
PMID:9774667
The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
GO:0006886 intracellular protein transport
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: Correct pathway family but too broad. Tom22 specifically functions in TOM-complex mitochondrial protein import, and more specific TOM/mitochondrial-import BPs are already annotated.
Reason: Generic intracellular protein transport is far less informative than the existing TOM-mediated import annotations.
Supporting Evidence:
PMID:10519552
Mitochondrial preproteins are imported by a multisubunit translocase of the outer membrane (TOM), including receptor proteins and a general import pore.
GO:0030150 protein import into mitochondrial matrix
IEA
GO_REF:0000002 		ACCEPT
Summary: Correct as a TOM-entry step for matrix-destined preproteins (duplicates the IBA/IMP annotations for the same term).
Supporting Evidence:
PMID:10519552
The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
GO:0005515 protein binding
IPI
PMID:11276259
Multistep assembly of the protein import channel of the mito... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic for Tom22. The biologically informative role here (Tom22 as the receptor that initiates Tom40 targeting/assembly) is already captured by mitochondrial outer membrane translocase complex and protein insertion into mitochondrial outer membrane annotations.
Reason: Per project curation guidance, avoid generic `protein binding`; specific complex membership and assembly roles are informative.
Supporting Evidence:
PMID:11276259
the channel-lining Tom40 is first targeted to the membrane via the receptor proteins Tom20 and Tom22; it then assembles with Tom5 to form the 250 kDa intermediate exposed to the intermembrane space.
GO:0005515 protein binding
IPI
PMID:15797382
Mitochondrial presequence translocase: switching between TOM... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic. The Tom22–Tim21 interaction documented in this paper is captured at the level of TOM-complex membership and PAM/presequence-translocase coupling annotations rather than generic protein binding.
Reason: Generic `protein binding` does not convey the biological role; the Tim21–Tom22 interaction is a downstream coupling event better captured by complex/process annotations.
Supporting Evidence:
PMID:10519552
Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery.
GO:0005515 protein binding
IPI
PMID:16093310
Large-scale identification of yeast integral membrane protei... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic for Tom22. The Tom22–Tom40 interaction is informatively captured by TOM-complex part_of annotations.
Reason: Use TOM complex / outer-membrane translocase membership instead of generic protein binding.
Supporting Evidence:
PMID:9774667
The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
GO:0005515 protein binding
IPI
PMID:17635912
The mitochondrial TOM complex is required for tBid/Bax-induc... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic. The relevant interactions (Tom22 with Tom40 and with apoptotic regulators such as Bax in cross-species systems) are better captured by complex membership and process-level annotations.
Reason: Generic `protein binding` does not convey the functional contribution; TOM-complex and import-process annotations already capture the informative role.
Supporting Evidence:
PMID:9774667
The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
GO:0005515 protein binding
IPI
PMID:22009199
The mitochondrial contact site complex, a determinant of mit... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic. The Tom22 interaction with the MICOS/mitofilin (Fcj1) machinery reported in this paper is better captured by the mitochondrial-membrane organisation and TOM/MICOS coupling annotations than by generic protein binding.
Reason: Per project guidance, avoid `protein binding`; use informative complex/process terms.
Supporting Evidence:
PMID:10519552
Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery.
GO:0005515 protein binding
IPI
PMID:22198199
The cytosolic domain of human Tom22 modulates human Bax mito... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic for Tom22. Cross-species Tom22–Bax interactions documented in this paper are captured at the level of TOM-complex membership and outer-membrane process annotations.
Reason: Generic `protein binding` is uninformative; use TOM complex / OMM-process annotations.
Supporting Evidence:
PMID:9774667
The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
GO:0005515 protein binding
IPI
PMID:23911324
Coupling of mitochondrial import and export translocases by ... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic. Tom22 interactions with Tom40, Tom20, and Sam50 captured here represent TOM/TOM-SAM supercomplex relationships best annotated at the complex-membership level.
Reason: TOM and SAM/TOM-SAM coupling annotations are more informative than generic protein binding.
Supporting Evidence:
PMID:9774667
The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
GO:0005515 protein binding
IPI
PMID:37968396
The social and structural architecture of the yeast protein ... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic. Large-scale interactome data implicating Tom22 with Tom40 and Tom20 corroborate TOM-complex membership annotations rather than supporting an independent informative MF.
Reason: Generic `protein binding` is uninformative; use TOM-complex annotations.
Supporting Evidence:
PMID:9774667
The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
GO:0005515 protein binding
IPI
PMID:9774667
Preprotein translocase of the outer mitochondrial membrane: ... 		MARK AS OVER ANNOTATED
Summary: Protein binding is too generic for Tom22. The Tom22–Tom40 and Tom22–Tom20 interactions documented in this study are already captured by TOM-complex membership annotations.
Reason: Generic `protein binding` is uninformative; TOM-complex annotations carry the same information with more specificity.
Supporting Evidence:
PMID:9774667
The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
GO:0005741 mitochondrial outer membrane
IDA
PMID:9774667
Preprotein translocase of the outer mitochondrial membrane: ... 		ACCEPT
Summary: Correct. Tom22 is an integral outer mitochondrial membrane component of the TOM complex.
Supporting Evidence:
PMID:9774667
The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
GO:0005742 mitochondrial outer membrane translocase complex
IPI
PMID:9774667
Preprotein translocase of the outer mitochondrial membrane: ... 		ACCEPT
Summary: Correct. Tom22 is a core subunit of the TOM/GIP complex as demonstrated by this study.
Supporting Evidence:
PMID:9774667
The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
GO:0045040 protein insertion into mitochondrial outer membrane
IDA
PMID:9774667
Preprotein translocase of the outer mitochondrial membrane: ... 		ACCEPT
Summary: Correct. Tom22 acts as a receptor required for targeting and assembly of Tom40 and other outer membrane import-machinery substrates into the OMM.
Supporting Evidence:
PMID:11276259
the channel-lining Tom40 is first targeted to the membrane via the receptor proteins Tom20 and Tom22; it then assembles with Tom5 to form the 250 kDa intermediate exposed to the intermembrane space.
GO:0045040 protein insertion into mitochondrial outer membrane
NAS
PMID:9774667
Preprotein translocase of the outer mitochondrial membrane: ... 		ACCEPT
Summary: Correct (duplicate of the IDA call from the same paper).
Supporting Evidence:
PMID:9774667
In mutant mitochondria lacking Tom6, the interaction between Tom22 and Tom40 is destabilized, leading to the dissociation of Tom22 and the generation of a subcomplex of approximately 100K containing Tom40, Tom7, and Tom5.
GO:0005741 mitochondrial outer membrane
IDA
PMID:16689936
Integral membrane proteins in the mitochondrial outer membra... 		ACCEPT
Summary: Correct. Confirms Tom22 as an integral mitochondrial outer membrane protein in yeast.
Supporting Evidence:
PMID:9774667
The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
GO:0005739 mitochondrion
HDA
PMID:24769239
Quantitative variations of the mitochondrial proteome and ph... 		MARK AS OVER ANNOTATED
Summary: Correct but very broad. More specific mitochondrial outer membrane annotations are present.
Reason: Tom22 is a single-pass outer-membrane protein; the specific GO:0005741 (mitochondrial outer membrane) annotations are more informative.
Supporting Evidence:
PMID:9774667
The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
GO:0005739 mitochondrion
HDA
PMID:16823961
Toward the complete yeast mitochondrial proteome: multidimen... 		MARK AS OVER ANNOTATED
Summary: Correct but very broad; more specific outer-membrane annotations exist.
Reason: Prefer GO:0005741 mitochondrial outer membrane.
Supporting Evidence:
PMID:9774667
The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
GO:0005741 mitochondrial outer membrane
HDA
PMID:16407407
Proteomic analysis of the yeast mitochondrial outer membrane... 		ACCEPT
Summary: Correct. Tom22 is an integral outer mitochondrial membrane protein.
Supporting Evidence:
PMID:9774667
The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
GO:0008320 protein transmembrane transporter activity
IMP
PMID:10519552
Tom22 is a multifunctional organizer of the mitochondrial pr... 		ACCEPT
Summary: Accepted as contribution to the TOM complex protein translocation activity. The IMP rests on tom22Ξ” growth/import phenotypes plus a tight control of channel gating, demonstrating that Tom22 is required for the TOM complex to perform transmembrane protein translocation even though Tom40 is the conducting pore.
Reason: Experimental annotation by SGD curator with the `contributes_to` qualifier, which is the correct semantic for a complex subunit that does not independently translocate substrate but is required for the activity of the complex that does. Upstream go-annotation issue #6466 raised concern about the IBA propagation of this term; this IMP is the source of the experimental support and aligns with that semantic.
Supporting Evidence:
PMID:10519552
The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
PMID:10519552
In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating.
GO:0005742 mitochondrial outer membrane translocase complex
IDA
PMID:9774667
Preprotein translocase of the outer mitochondrial membrane: ... 		ACCEPT
Summary: Correct. Direct demonstration that Tom22 is a core member of the TOM/GIP complex.
Supporting Evidence:
PMID:9774667
The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
GO:0030150 protein import into mitochondrial matrix
IMP
PMID:10519552
Tom22 is a multifunctional organizer of the mitochondrial pr... 		ACCEPT
Summary: Correct. tom22Ξ” mitochondria are strongly defective for preprotein import; matrix-destined preproteins use the TOM complex at the entry step, with Tom22 acting as the central receptor.
Supporting Evidence:
PMID:10519552
Here we report the unexpected observation that a yeast strain can survive without Tom22, although it is strongly reduced in growth and the import of mitochondrial proteins.
GO:0030150 protein import into mitochondrial matrix
IMP
PMID:9774667
Preprotein translocase of the outer mitochondrial membrane: ... 		ACCEPT
Summary: Correct. The TOM complex is the entry step for matrix-destined preproteins; Tom22 is one of two essential subunits of the GIP complex.
Supporting Evidence:
PMID:9774667
Besides the essential proteins Tom22 and Tom40, the GIP complex contains three small subunits, Tom5, Tom6, and Tom7.
GO:0045040 protein insertion into mitochondrial outer membrane
IMP
PMID:12628251
Biogenesis of yeast mitochondrial cytochrome c: a unique rel... 		ACCEPT
Summary: Correct. Tom22 is required for biogenesis of OMM/IMS substrates routed through the TOM machinery; cytochrome c levels are greatly reduced in tom22 mutants.
Supporting Evidence:
PMID:12628251
Mitochondria lacking the central receptor and organizing protein Tom22 contain greatly reduced levels of cytochrome c.
GO:0005741 mitochondrial outer membrane
TAS
Reactome:R-SCE-1252255 		ACCEPT
Summary: Correct. Tom22 is an outer mitochondrial membrane component of the TOM complex.
Supporting Evidence:
PMID:9774667
The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
GO:0005741 mitochondrial outer membrane
TAS
Reactome:R-SCE-8953627 		ACCEPT
Summary: Correct. Tom22 in the MIB context is still anchored in the mitochondrial outer membrane.
Supporting Evidence:
PMID:9774667
The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).

Core Functions

Tom22 is the central preprotein receptor and organizing scaffold of the TOM complex, recognizing presequence-bearing and internal-signal mitochondrial precursors via its cytosolic and IMS domains and transferring them toward the Tom40 translocation pore.

Molecular Function:
mitochondrion targeting sequence binding
Directly Involved In:
protein import into mitochondrial matrix protein insertion into mitochondrial outer membrane
Cellular Locations:
mitochondrial outer membrane
In Complex:
mitochondrial outer membrane translocase complex
Supporting Evidence:
  • PMID:10519552
    The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
  • PMID:10519552
    Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery.
  • file:human/TOMM22/TOMM22-deep-research-falcon.md
    TOMM22 functions as a **major preprotein-binding site** and **organizational scaffold** for the TOM complex, helping recognize mitochondrial precursor proteins and transfer them toward the **Tom40 import pore**.

Tom22 contributes to TOM complex protein transmembrane transport activity. Tom40 is the conducting pore; Tom22 is the receptor/scaffold required for preprotein delivery to that pore and for tight control of channel gating, so the `contributes_to` qualifier on GO:0008320 is the appropriate semantic.

Cellular Locations:
mitochondrial outer membrane
In Complex:
mitochondrial outer membrane translocase complex
Supporting Evidence:
  • PMID:10519552
    In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating.
  • PMID:9774667
    The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.

Tom22 is required for TOM complex assembly and stability, docking Tom20 and Tom70 onto the TOM core and supporting Tom40 biogenesis/outer-membrane insertion through the TOM-SAM pathway.

Directly Involved In:
protein insertion into mitochondrial outer membrane
Cellular Locations:
mitochondrial outer membrane
In Complex:
mitochondrial outer membrane translocase complex
Supporting Evidence:
  • PMID:9774667
    The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
  • PMID:11276259
    the channel-lining Tom40 is first targeted to the membrane via the receptor proteins Tom20 and Tom22; it then assembles with Tom5 to form the 250 kDa intermediate exposed to the intermembrane space.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10519552
Tom22 is a multifunctional organizer of the mitochondrial preprotein translocase.
  • Tom22 is the central preprotein receptor of the TOM complex, binding preproteins through both its cytosolic and intermembrane space domains and stably associated with the Tom40 channel.
    "The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40"
  • Tom22 is required for the higher-level organization of the TOM machinery and for tight control of Tom40 channel gating.
    "In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating."
  • Tom22's cytosolic domain serves as the docking point for the peripheral receptors Tom20 and Tom70 onto the TOM/GIP core.
    "its cytosolic domain serves as docking point for the peripheral receptors Tom20 and Tom70."
PMID:11276259
Multistep assembly of the protein import channel of the mitochondrial outer membrane.
  • Tom40 is first targeted to the OMM via the receptor proteins Tom20 and Tom22, supporting Tom22's role in protein insertion into the outer membrane.
    "the channel-lining Tom40 is first targeted to the membrane via the receptor proteins Tom20 and Tom22; it then assembles with Tom5 to form the 250 kDa intermediate exposed to the intermembrane space."
PMID:12628251
Biogenesis of yeast mitochondrial cytochrome c: a unique relationship to the TOM machinery.
  • tom22 mutants have greatly reduced cytochrome c levels, supporting Tom22's role in TOM-mediated import beyond canonical matrix presequence routes.
    "Mitochondria lacking the central receptor and organizing protein Tom22 contain greatly reduced levels of cytochrome c."
PMID:15797382
Mitochondrial presequence translocase: switching between TOM tethering and motor recruitment involves Tim21 and Tim17.
PMID:16093310
Large-scale identification of yeast integral membrane protein interactions.
PMID:16407407
Proteomic analysis of the yeast mitochondrial outer membrane reveals accumulation of a subclass of preproteins.
PMID:16689936
Integral membrane proteins in the mitochondrial outer membrane of Saccharomyces cerevisiae.
PMID:16823961
Toward the complete yeast mitochondrial proteome: multidimensional separation techniques for mitochondrial proteomics.
PMID:17635912
The mitochondrial TOM complex is required for tBid/Bax-induced cytochrome c release.
PMID:22009199
The mitochondrial contact site complex, a determinant of mitochondrial architecture.
PMID:22198199
The cytosolic domain of human Tom22 modulates human Bax mitochondrial translocation and conformation in yeast.
PMID:23911324
Coupling of mitochondrial import and export translocases by receptor-mediated supercomplex formation.
PMID:24769239
Quantitative variations of the mitochondrial proteome and phosphoproteome during fermentative and respiratory growth in Saccharomyces cerevisiae.
PMID:37968396
The social and structural architecture of the yeast protein interactome.
PMID:9774667
Preprotein translocase of the outer mitochondrial membrane: molecular dissection and assembly of the general import pore complex.
  • Tom22 is a core, essential subunit of the GIP complex stably associated with Tom40.
    "The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes."
  • The TOM/GIP complex containing Tom40, Tom22, and three small Tom proteins forms the central unit of the OMM import machinery.
    "The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery."
Reactome:R-SCE-1252255
TOM40:TOM70 complex translocates proteins from the cytosol to the mitochondrial intermembrane space
Reactome:R-SCE-8953627
Formation of MIB complex containing the MICOS complex
file:human/TOMM22/TOMM22-deep-research-falcon.md
Falcon deep research report for human TOMM22 (used as ortholog reference for yeast Tom22)
  • TOMM22 functions as the central receptor of the TOM complex, recognizing mitochondrial precursor proteins and transferring them toward the Tom40 import pore.
    "TOMM22 functions as a **major preprotein-binding site** and **organizational scaffold** for the TOM complex, helping recognize mitochondrial precursor proteins and transfer them toward the **Tom40 import pore**."

Suggested Questions for Experts

Q: How separable are Tom22's preprotein-receptor and TOM-complex scaffold functions in yeast, and does the IMS domain alone account for the trans presequence binding step?

Q: For the TOM-SAM handoff that inserts Tom40 Ξ²-barrels, which Tom22 surface is required, and is this distinct from the cytosolic Tom20/Tom70 docking surface?

Suggested Experiments

Experiment: In purified reconstituted TOM proteoliposomes, compare preprotein translocation rates of Tom40-only vs. Tom22+Tom40 (and full TOM minus Tom22) at varying preprotein concentrations to quantify Tom22's kinetic contribution beyond gating.

Hypothesis: The `contributes_to` semantic on GO:0008320 reflects a genuine functional dependence of TOM-mediated transport on Tom22, not just a complex-membership artifact.

πŸ“š Additional Documentation

Notes

(TOM22-notes.md)

TOM22 (yeast) β€” review notes

Trigger

This review was created to address upstream issue
geneontology/go-annotation#6466,
"PAINT issue: PTN004364609 GO:0008320 | transmembrane protein transporter
activity for Tom40", which states:

tom40 is the channel, we don't know the MF of tom22

The PANTHER family PTN004364609 IBA propagation reaches yeast Tom22 via
SGD:S000005075. The upstream curator's concern is whether GO:0008320
"transmembrane protein transporter activity" should propagate to Tom22 at all,
since Tom40 is the conducting pore.

Decision

Retain both GO:0008320 annotations on yeast Tom22 with the contributes_to
qualifier:

  1. contributes_to GO:0008320 β€” IBA from PTN004364609 (GO_REF:0000033) β€” ACCEPT.
  2. contributes_to GO:0008320 β€” IMP from PMID:10519552 (SGD assignment) β€” ACCEPT.

Reasoning:

  • The contributes_to qualifier in GO semantics encodes exactly the case the
    upstream curator is concerned about: a subunit that does not independently
    perform the MF but is required for the activity of the complex that does.
    Tom22 fits that pattern β€” it is a receptor/scaffold for the TOM complex, the
    complex as a whole performs transmembrane protein transport, and Tom40 is the
    conducting pore.
  • The IBA is not the only source of this annotation. SGD already has an
    experimental IMP annotation with contributes_to from PMID:10519552
    (van Wilpe et al. 1999, "Tom22 is a multifunctional organizer of the
    mitochondrial preprotein translocase", Nature). Per CLAUDE.md curation
    guidance, an experimental annotation by a real curator should not be removed
    on the basis of an abstract-only read.
  • PMID:10519552 establishes that "the translocase dissociates into core
    complexes ... but lacks a tight control of channel gating" in the absence of
    Tom22, i.e. Tom22 is required for the activity of the TOM transmembrane
    protein translocase even though Tom40 is the pore.
  • The human ortholog review (genes/human/TOMM22/TOMM22-ai-review.yaml) reaches
    the same conclusion: ACCEPT contributes_to GO:0008320 rather than remove.

The biologically appropriate response to the upstream concern is to keep
contributes_to on Tom22 and reserve enables GO:0008320 for Tom40.

Other key calls

  • All enables GO:0005515 protein binding IPIs β€” MARK_AS_OVER_ANNOTATED. Per
    CLAUDE.md guidance, generic protein binding is uninformative; the TOM and
    TOM-SAM complex membership annotations capture the same information with more
    specificity.
  • GO:0006886 intracellular protein transport IEA β€” MARK_AS_OVER_ANNOTATED.
    Generic; specific TOM-mediated import BPs are already present.
  • GO:0005739 mitochondrion HDA Γ— 2 β€” MARK_AS_OVER_ANNOTATED. Parent of the
    more specific GO:0005741 mitochondrial outer membrane annotations that are
    also present.
  • All GO:0005742 mitochondrial outer membrane translocase complex,
    GO:0005741 mitochondrial outer membrane, and GO:0045040 protein insertion into mitochondrial outer membrane annotations β€” ACCEPT.
  • GO:0030150 protein import into mitochondrial matrix IBA/IEA/IMP β€” ACCEPT
    with the understanding that matrix import is one of several TOM-mediated
    routes through Tom22; the matrix term is well-supported by the experimental
    IMPs in tom22Ξ”.

Data provenance

  • Cached publications used (verbatim supporting_text):
    PMID:9774667, PMID:10519552, PMID:11276259, PMID:12628251.
  • Cross-reference: genes/human/TOMM22/TOMM22-ai-review.yaml (ortholog review)
    and genes/human/TOMM22/TOMM22-deep-research-falcon.md (used for orthologue
    context; quoted verbatim).
  • Deep research providers (falcon, perplexity-lite) returned no result for
    yeast TOM22 due to missing API keys. Per CLAUDE.md, no
    *-deep-research-{provider}.md file was authored.

Open questions for the upstream curator

  • Should the PTN004364609 IBA for GO:0008320 be left in place with
    contributes_to on all non-Tom40 subunits (the conservative interpretation
    consistent with the SGD IMP and the human TOMM22 review), or only on
    receptors that have direct experimental support? If the latter, Tom22 should
    still keep the term because PMID:10519552 is a direct IMP.
  • For the related GO:0030943 mitochondrion targeting sequence binding
    proposed obsoletion (go-annotation#6437 β†’ go-ontology#32108), once the NTR
    replacement term is minted, Tom22 will need a MODIFY pass on the
    core_functions.molecular_function slot.

πŸ“„ View Raw YAML

 
id: P49334
gene_symbol: TOM22
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: Yeast TOM22 (Mom22/Mas17/Mas22) encodes Tom22, a single-pass type II outer mitochondrial membrane protein that serves as the central receptor and organizing scaffold of the translocase of the outer mitochondrial membrane (TOM) complex. Together with Tom20 and Tom70, it forms the transit peptide receptor at the outer membrane surface, recognizes cytosolically synthesized mitochondrial preproteins, and transfers them toward the Tom40 translocation pore. Its cytosolic domain docks Tom20 and Tom70 to the general import pore (GIP) complex, its intermembrane space domain provides a trans binding site for presequences, and its transmembrane anchor is required to stabilize the higher-order TOM machinery and to control Tom40 channel gating. Tom22 also contributes to Tom40 biogenesis and Tom40 Ξ²-barrel insertion into the outer membrane through TOM–SAM handoff.
existing_annotations:
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct. Tom22 is a core receptor/scaffold subunit of the TOM (translocase of outer mitochondrial membrane) complex.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
    - reference_id: PMID:9774667
      supporting_text: The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct as a TOM-entry step for matrix-destined mitochondrial preproteins. Tom22 is a receptor/scaffold that recognizes preproteins and transfers them toward the Tom40 pore for downstream TIM23/PAM-mediated matrix import. Tom22 also participates in non-matrix import routes, so this BP captures one of several TOM-mediated pathways.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10519552
      supporting_text: The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
    - reference_id: PMID:10519552
      supporting_text: Here we report the unexpected observation that a yeast strain can survive without Tom22, although it is strongly reduced in growth and the import of mitochondrial proteins.
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Accepted as a contribution to TOM complex protein transmembrane transporter activity. Tom22 is the central receptor/scaffold that recognizes preproteins and transfers them to the Tom40 pore; the `contributes_to` qualifier is the appropriate semantic for a complex subunit that does not independently carry out transmembrane transport but is required for the activity of the complex that does.
    action: ACCEPT
    reason: 'Upstream go-annotation issue #6466 raised the concern that "tom40 is the channel, we don''t know the MF of tom22" and suggested removing this IBA propagation. The annotation is retained because (a) it carries the `contributes_to` qualifier, which by GO semantics indicates a subunit-level contribution to a complex-level activity (not a claim that Tom22 independently translocates substrate); (b) the same propagation is annotated by SGD as an experimental IMP (PMID:10519552) β€” Tom22 is required for tight control of channel gating and the higher-order organisation that sustains import; and (c) the parallel human TOMM22 review (genes/human/TOMM22/TOMM22-ai-review.yaml) reaches the same conclusion. Tom40 should retain `enables GO:0008320` while Tom22 retains `contributes_to GO:0008320`.'
    additional_reference_ids:
    - file:human/TOMM22/TOMM22-deep-research-falcon.md
    - PMID:10519552
    supported_by:
    - reference_id: PMID:10519552
      supporting_text: In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating.
    - reference_id: PMID:10519552
      supporting_text: Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery.
    - reference_id: file:human/TOMM22/TOMM22-deep-research-falcon.md
      supporting_text: TOMM22 functions as a **major preprotein-binding site** and **organizational scaffold** for the TOM complex, helping recognize mitochondrial precursor proteins and transfer them toward the **Tom40 import pore**.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Correct. Tom22 is a single-pass type II mitochondrial outer membrane protein.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Correct. Tom22 is a core subunit of the TOM/translocase complex.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Correct pathway family but too broad. Tom22 specifically functions in TOM-complex mitochondrial protein import, and more specific TOM/mitochondrial-import BPs are already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic intracellular protein transport is far less informative than the existing TOM-mediated import annotations.
    supported_by:
    - reference_id: PMID:10519552
      supporting_text: Mitochondrial preproteins are imported by a multisubunit translocase of the outer membrane (TOM), including receptor proteins and a general import pore.
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Correct as a TOM-entry step for matrix-destined preproteins (duplicates the IBA/IMP annotations for the same term).
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10519552
      supporting_text: The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11276259
  qualifier: enables
  review:
    summary: Protein binding is too generic for Tom22. The biologically informative role here (Tom22 as the receptor that initiates Tom40 targeting/assembly) is already captured by mitochondrial outer membrane translocase complex and protein insertion into mitochondrial outer membrane annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project curation guidance, avoid generic `protein binding`; specific complex membership and assembly roles are informative.
    supported_by:
    - reference_id: PMID:11276259
      supporting_text: the channel-lining Tom40 is first targeted to the membrane via the receptor proteins Tom20 and Tom22; it then assembles with Tom5 to form the 250 kDa intermediate exposed to the intermembrane space.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15797382
  qualifier: enables
  review:
    summary: Protein binding is too generic. The Tom22–Tim21 interaction documented in this paper is captured at the level of TOM-complex membership and PAM/presequence-translocase coupling annotations rather than generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic `protein binding` does not convey the biological role; the Tim21–Tom22 interaction is a downstream coupling event better captured by complex/process annotations.
    supported_by:
    - reference_id: PMID:10519552
      supporting_text: Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16093310
  qualifier: enables
  review:
    summary: Protein binding is too generic for Tom22. The Tom22–Tom40 interaction is informatively captured by TOM-complex part_of annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Use TOM complex / outer-membrane translocase membership instead of generic protein binding.
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17635912
  qualifier: enables
  review:
    summary: Protein binding is too generic. The relevant interactions (Tom22 with Tom40 and with apoptotic regulators such as Bax in cross-species systems) are better captured by complex membership and process-level annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic `protein binding` does not convey the functional contribution; TOM-complex and import-process annotations already capture the informative role.
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22009199
  qualifier: enables
  review:
    summary: Protein binding is too generic. The Tom22 interaction with the MICOS/mitofilin (Fcj1) machinery reported in this paper is better captured by the mitochondrial-membrane organisation and TOM/MICOS coupling annotations than by generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per project guidance, avoid `protein binding`; use informative complex/process terms.
    supported_by:
    - reference_id: PMID:10519552
      supporting_text: Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22198199
  qualifier: enables
  review:
    summary: Protein binding is too generic for Tom22. Cross-species Tom22–Bax interactions documented in this paper are captured at the level of TOM-complex membership and outer-membrane process annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic `protein binding` is uninformative; use TOM complex / OMM-process annotations.
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23911324
  qualifier: enables
  review:
    summary: Protein binding is too generic. Tom22 interactions with Tom40, Tom20, and Sam50 captured here represent TOM/TOM-SAM supercomplex relationships best annotated at the complex-membership level.
    action: MARK_AS_OVER_ANNOTATED
    reason: TOM and SAM/TOM-SAM coupling annotations are more informative than generic protein binding.
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37968396
  qualifier: enables
  review:
    summary: Protein binding is too generic. Large-scale interactome data implicating Tom22 with Tom40 and Tom20 corroborate TOM-complex membership annotations rather than supporting an independent informative MF.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic `protein binding` is uninformative; use TOM-complex annotations.
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9774667
  qualifier: enables
  review:
    summary: Protein binding is too generic for Tom22. The Tom22–Tom40 and Tom22–Tom20 interactions documented in this study are already captured by TOM-complex membership annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic `protein binding` is uninformative; TOM-complex annotations carry the same information with more specificity.
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IDA
  original_reference_id: PMID:9774667
  qualifier: located_in
  review:
    summary: Correct. Tom22 is an integral outer mitochondrial membrane component of the TOM complex.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IPI
  original_reference_id: PMID:9774667
  qualifier: part_of
  review:
    summary: Correct. Tom22 is a core subunit of the TOM/GIP complex as demonstrated by this study.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
- term:
    id: GO:0045040
    label: protein insertion into mitochondrial outer membrane
  evidence_type: IDA
  original_reference_id: PMID:9774667
  qualifier: involved_in
  review:
    summary: Correct. Tom22 acts as a receptor required for targeting and assembly of Tom40 and other outer membrane import-machinery substrates into the OMM.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11276259
      supporting_text: the channel-lining Tom40 is first targeted to the membrane via the receptor proteins Tom20 and Tom22; it then assembles with Tom5 to form the 250 kDa intermediate exposed to the intermembrane space.
- term:
    id: GO:0045040
    label: protein insertion into mitochondrial outer membrane
  evidence_type: NAS
  original_reference_id: PMID:9774667
  qualifier: involved_in
  review:
    summary: Correct (duplicate of the IDA call from the same paper).
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: In mutant mitochondria lacking Tom6, the interaction between Tom22 and Tom40 is destabilized, leading to the dissociation of Tom22 and the generation of a subcomplex of approximately 100K containing Tom40, Tom7, and Tom5.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IDA
  original_reference_id: PMID:16689936
  qualifier: located_in
  review:
    summary: Correct. Confirms Tom22 as an integral mitochondrial outer membrane protein in yeast.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:24769239
  qualifier: located_in
  review:
    summary: Correct but very broad. More specific mitochondrial outer membrane annotations are present.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tom22 is a single-pass outer-membrane protein; the specific GO:0005741 (mitochondrial outer membrane) annotations are more informative.
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:16823961
  qualifier: located_in
  review:
    summary: Correct but very broad; more specific outer-membrane annotations exist.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer GO:0005741 mitochondrial outer membrane.
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: HDA
  original_reference_id: PMID:16407407
  qualifier: located_in
  review:
    summary: Correct. Tom22 is an integral outer mitochondrial membrane protein.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:10519552
  qualifier: contributes_to
  review:
    summary: Accepted as contribution to the TOM complex protein translocation activity. The IMP rests on tom22Ξ” growth/import phenotypes plus a tight control of channel gating, demonstrating that Tom22 is required for the TOM complex to perform transmembrane protein translocation even though Tom40 is the conducting pore.
    action: ACCEPT
    reason: 'Experimental annotation by SGD curator with the `contributes_to` qualifier, which is the correct semantic for a complex subunit that does not independently translocate substrate but is required for the activity of the complex that does. Upstream go-annotation issue #6466 raised concern about the IBA propagation of this term; this IMP is the source of the experimental support and aligns with that semantic.'
    supported_by:
    - reference_id: PMID:10519552
      supporting_text: The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
    - reference_id: PMID:10519552
      supporting_text: In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating.
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IDA
  original_reference_id: PMID:9774667
  qualifier: part_of
  review:
    summary: Correct. Direct demonstration that Tom22 is a core member of the TOM/GIP complex.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IMP
  original_reference_id: PMID:10519552
  qualifier: involved_in
  review:
    summary: Correct. tom22Ξ” mitochondria are strongly defective for preprotein import; matrix-destined preproteins use the TOM complex at the entry step, with Tom22 acting as the central receptor.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10519552
      supporting_text: Here we report the unexpected observation that a yeast strain can survive without Tom22, although it is strongly reduced in growth and the import of mitochondrial proteins.
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IMP
  original_reference_id: PMID:9774667
  qualifier: involved_in
  review:
    summary: Correct. The TOM complex is the entry step for matrix-destined preproteins; Tom22 is one of two essential subunits of the GIP complex.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: Besides the essential proteins Tom22 and Tom40, the GIP complex contains three small subunits, Tom5, Tom6, and Tom7.
- term:
    id: GO:0045040
    label: protein insertion into mitochondrial outer membrane
  evidence_type: IMP
  original_reference_id: PMID:12628251
  qualifier: involved_in
  review:
    summary: Correct. Tom22 is required for biogenesis of OMM/IMS substrates routed through the TOM machinery; cytochrome c levels are greatly reduced in tom22 mutants.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12628251
      supporting_text: Mitochondria lacking the central receptor and organizing protein Tom22 contain greatly reduced levels of cytochrome c.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-SCE-1252255
  qualifier: located_in
  review:
    summary: Correct. Tom22 is an outer mitochondrial membrane component of the TOM complex.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-SCE-8953627
  qualifier: located_in
  review:
    summary: Correct. Tom22 in the MIB context is still anchored in the mitochondrial outer membrane.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9774667
      supporting_text: The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP).
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10519552
  title: Tom22 is a multifunctional organizer of the mitochondrial preprotein translocase.
  findings:
  - statement: Tom22 is the central preprotein receptor of the TOM complex, binding preproteins through both its cytosolic and intermembrane space domains and stably associated with the Tom40 channel.
    supporting_text: The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
    reference_section_type: ABSTRACT
  - statement: Tom22 is required for the higher-level organization of the TOM machinery and for tight control of Tom40 channel gating.
    supporting_text: In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating.
    reference_section_type: ABSTRACT
  - statement: Tom22's cytosolic domain serves as the docking point for the peripheral receptors Tom20 and Tom70 onto the TOM/GIP core.
    supporting_text: its cytosolic domain serves as docking point for the peripheral receptors Tom20 and Tom70.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary research; underpins the SGD IMP for Tom22 contributes_to GO:0008320 and the IMP for involved_in GO:0030150.
- id: PMID:11276259
  title: Multistep assembly of the protein import channel of the mitochondrial outer
    membrane.
  findings:
  - statement: Tom40 is first targeted to the OMM via the receptor proteins Tom20 and Tom22, supporting Tom22's role in protein insertion into the outer membrane.
    supporting_text: the channel-lining Tom40 is first targeted to the membrane via the receptor proteins Tom20 and Tom22; it then assembles with Tom5 to form the 250 kDa intermediate exposed to the intermembrane space.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary research; supports the Tom22 role in Tom40 biogenesis / OMM protein insertion.
- id: PMID:12628251
  title: 'Biogenesis of yeast mitochondrial cytochrome c: a unique relationship to
    the TOM machinery.'
  findings:
  - statement: tom22 mutants have greatly reduced cytochrome c levels, supporting Tom22's role in TOM-mediated import beyond canonical matrix presequence routes.
    supporting_text: Mitochondria lacking the central receptor and organizing protein Tom22 contain greatly reduced levels of cytochrome c.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary research; supports the IMP for GO:0045040 protein insertion into mitochondrial outer membrane.
- id: PMID:15797382
  title: 'Mitochondrial presequence translocase: switching between TOM tethering and
    motor recruitment involves Tim21 and Tim17.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports Tom22 interaction with Tim21 (TIM23 coupling). Used here only to anchor the protein-binding interaction call.
- id: PMID:16093310
  title: Large-scale identification of yeast integral membrane protein interactions.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome data; supports Tom22–Tom40 binding at the complex level only.
- id: PMID:16407407
  title: Proteomic analysis of the yeast mitochondrial outer membrane reveals accumulation
    of a subclass of preproteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Outer-membrane proteomics confirming Tom22 OMM localization.
- id: PMID:16689936
  title: Integral membrane proteins in the mitochondrial outer membrane of Saccharomyces
    cerevisiae.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Outer-membrane proteomics confirming Tom22 OMM localization.
- id: PMID:16823961
  title: 'Toward the complete yeast mitochondrial proteome: multidimensional separation
    techniques for mitochondrial proteomics.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Mitochondrial proteome HDA; supports mitochondrion (parent) localization only.
- id: PMID:17635912
  title: The mitochondrial TOM complex is required for tBid/Bax-induced cytochrome
    c release.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Documents Tom22–Tom40 and Tom22–Bax interactions; protein binding annotation downgraded to over-annotated.
- id: PMID:22009199
  title: The mitochondrial contact site complex, a determinant of mitochondrial architecture.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Documents Tom22 interaction with Fcj1/MICOS subunits; complex/process annotations capture this better than generic binding.
- id: PMID:22198199
  title: The cytosolic domain of human Tom22 modulates human Bax mitochondrial translocation
    and conformation in yeast.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cross-species human Tom22 study; supports the generic protein-binding call but is not core for yeast Tom22 function.
- id: PMID:23911324
  title: Coupling of mitochondrial import and export translocases by receptor-mediated
    supercomplex formation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Documents TOM–SAM supercomplex coupling involving Tom22; complex-level annotations preferred over generic protein binding.
- id: PMID:24769239
  title: Quantitative variations of the mitochondrial proteome and phosphoproteome
    during fermentative and respiratory growth in Saccharomyces cerevisiae.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Mitochondrial proteome HDA; supports broad mitochondrion localization only.
- id: PMID:37968396
  title: The social and structural architecture of the yeast protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome supporting Tom22–TOM-subunit interactions at complex level.
- id: PMID:9774667
  title: 'Preprotein translocase of the outer mitochondrial membrane: molecular dissection
    and assembly of the general import pore complex.'
  findings:
  - statement: Tom22 is a core, essential subunit of the GIP complex stably associated with Tom40.
    supporting_text: The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
    reference_section_type: ABSTRACT
  - statement: The TOM/GIP complex containing Tom40, Tom22, and three small Tom proteins forms the central unit of the OMM import machinery.
    supporting_text: The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary research; underpins multiple ACCEPT calls (TOM complex membership, OMM localization, Tom40 OMM assembly).
- id: Reactome:R-SCE-1252255
  title: TOM40:TOM70 complex translocates proteins from the cytosol to the mitochondrial
    intermembrane space
  findings: []
- id: Reactome:R-SCE-8953627
  title: Formation of MIB complex containing the MICOS complex
  findings: []
- id: file:human/TOMM22/TOMM22-deep-research-falcon.md
  title: Falcon deep research report for human TOMM22 (used as ortholog reference for yeast Tom22)
  findings:
  - statement: TOMM22 functions as the central receptor of the TOM complex, recognizing mitochondrial precursor proteins and transferring them toward the Tom40 import pore.
    supporting_text: TOMM22 functions as a **major preprotein-binding site** and **organizational scaffold** for the TOM complex, helping recognize mitochondrial precursor proteins and transfer them toward the **Tom40 import pore**.
    reference_section_type: OTHER
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Deep-research summary of the human ortholog; used here to anchor receptor/scaffold reasoning where yeast publications are abstract-only.
core_functions:
- description: Tom22 is the central preprotein receptor and organizing scaffold of the TOM complex, recognizing presequence-bearing and internal-signal mitochondrial precursors via its cytosolic and IMS domains and transferring them toward the Tom40 translocation pore.
  supported_by:
  - reference_id: PMID:10519552
    supporting_text: The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40
  - reference_id: PMID:10519552
    supporting_text: Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery.
  - reference_id: file:human/TOMM22/TOMM22-deep-research-falcon.md
    supporting_text: TOMM22 functions as a **major preprotein-binding site** and **organizational scaffold** for the TOM complex, helping recognize mitochondrial precursor proteins and transfer them toward the **Tom40 import pore**.
  molecular_function:
    id: GO:0030943
    label: mitochondrion targeting sequence binding
  directly_involved_in:
  - id: GO:0030150
    label: protein import into mitochondrial matrix
  - id: GO:0045040
    label: protein insertion into mitochondrial outer membrane
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  in_complex:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
- description: Tom22 contributes to TOM complex protein transmembrane transport activity. Tom40 is the conducting pore; Tom22 is the receptor/scaffold required for preprotein delivery to that pore and for tight control of channel gating, so the `contributes_to` qualifier on GO:0008320 is the appropriate semantic.
  supported_by:
  - reference_id: PMID:10519552
    supporting_text: In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating.
  - reference_id: PMID:9774667
    supporting_text: The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery.
  contributes_to_molecular_function:
    id: GO:0008320
    label: protein transmembrane transporter activity
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  in_complex:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
- description: Tom22 is required for TOM complex assembly and stability, docking Tom20 and Tom70 onto the TOM core and supporting Tom40 biogenesis/outer-membrane insertion through the TOM-SAM pathway.
  supported_by:
  - reference_id: PMID:9774667
    supporting_text: The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes.
  - reference_id: PMID:11276259
    supporting_text: the channel-lining Tom40 is first targeted to the membrane via the receptor proteins Tom20 and Tom22; it then assembles with Tom5 to form the 250 kDa intermediate exposed to the intermembrane space.
  directly_involved_in:
  - id: GO:0045040
    label: protein insertion into mitochondrial outer membrane
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  in_complex:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
proposed_new_terms: []
suggested_questions:
- question: How separable are Tom22's preprotein-receptor and TOM-complex scaffold functions in yeast, and does the IMS domain alone account for the trans presequence binding step?
  experts: []
- question: For the TOM-SAM handoff that inserts Tom40 Ξ²-barrels, which Tom22 surface is required, and is this distinct from the cytosolic Tom20/Tom70 docking surface?
  experts: []
suggested_experiments:
- hypothesis: The `contributes_to` semantic on GO:0008320 reflects a genuine functional dependence of TOM-mediated transport on Tom22, not just a complex-membership artifact.
  description: In purified reconstituted TOM proteoliposomes, compare preprotein translocation rates of Tom40-only vs. Tom22+Tom40 (and full TOM minus Tom22) at varying preprotein concentrations to quantify Tom22's kinetic contribution beyond gating.