TIM10

id: P87108
gene_symbol: TIM10
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
aliases:
- MRS11
- YHR005C-A
description: >-
  TIM10 is an essential mitochondrial intermembrane space (IMS) chaperone protein
  in Saccharomyces cerevisiae. It forms a heterohexameric complex with TIM9 (3x TIM9 +
  3x TIM10), known as the TIM9-TIM10 complex or soluble 70 kDa complex. This complex
  functions as an ATP-independent holdase chaperone that escorts hydrophobic multi-pass
  transmembrane precursor proteins (such as the ADP/ATP carrier and other members of
  the mitochondrial carrier family) across the aqueous IMS from the TOM complex at the
  outer membrane to the TIM22 complex at the inner membrane, where they are inserted.
  TIM10 acts as a substrate sensor within the complex, recognizing the transmembrane
  domains of carrier precursors. The protein contains a characteristic twin CX3C motif
  with four conserved cysteines that form two intramolecular disulfide bonds in the
  oxidizing IMS environment; during cytoplasmic transit, these cysteines coordinate
  zinc to maintain an import-competent reduced state. TIM10 also participates in the
  transfer of beta-barrel outer membrane protein precursors to the SAM complex. The
  TIM9-TIM10 complex associates with TIM12 to dock at the TIM22 translocase for
  precursor handoff and inner membrane insertion.
existing_annotations:
- term:
    id: GO:0042721
    label: TIM22 mitochondrial import inner membrane insertion complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      TIM10 is a peripheral component of the TIM22 complex. The soluble TIM9-TIM10
      complex docks onto the TIM22 inner membrane complex via TIM12 to deliver carrier
      precursors (PMID:9822593, PMID:9889188, PMID:12637749). Koehler et al. showed
      Tim10p is part of the 300 kDa TIM22 complex (PMID:9822593). Rehling et al.
      confirmed TIM10 as a component of the twin-pore TIM22 translocase (PMID:12637749).
    action: ACCEPT
    reason: >-
      TIM10 is a bona fide component of the TIM22 complex. It forms part of the
      peripheral chaperone subcomplex (TIM9-TIM10-TIM12) that is stably associated
      with the membrane-integral TIM22 complex. The IBA annotation is consistent
      with extensive experimental evidence.
    supported_by:
    - reference_id: PMID:9822593
      supporting_text: >-
        A small fraction of Tim9p is bound to the outer face of the inner membrane in a
        300 kDa complex whose other subunits include Tim54p, Tim22p, Tim12p and Tim10p.
    - reference_id: PMID:12637749
      supporting_text: >-
        Protein insertion into the mitochondrial inner membrane by a twin-pore translocase.
- term:
    id: GO:0032977
    label: membrane insertase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0032977 (membrane insertase activity) is defined as binding transmembrane
      domain-containing proteins and mediating their integration into a membrane.
      TIM10 does not itself insert proteins into the membrane. Rather, TIM10 escorts
      hydrophobic precursors across the IMS and delivers them to the TIM22 complex,
      which performs the actual membrane insertion (PMID:9430585, PMID:9495346).
      TIM10 functions as a chaperone/carrier in the aqueous IMS, not as an insertase.
    action: MODIFY
    reason: >-
      TIM10 does not have insertase activity. Tim22 is the insertase that mediates
      membrane-potential-dependent insertion of carrier proteins into the inner membrane.
      TIM10 is a soluble IMS chaperone that escorts precursors to TIM22. The correct
      molecular function is unfolded protein carrier activity (GO:0140309), which
      captures the escort/holdase function of TIM10. Koehler et al. explicitly stated
      that Tim10p was required to transport carrier precursors across the outer membrane,
      while Tim12p and Tim22p mediated insertion (PMID:9430585).
    proposed_replacement_terms:
    - id: GO:0140309
      label: unfolded protein carrier activity
    supported_by:
    - reference_id: PMID:9430585
      supporting_text: >-
        Tim10p readily dissociated from the complex and was required to transport carrier
        precursors across the outer membrane; Tim12p was firmly bound to Tim22p and
        mediated the insertion of carriers into the inner membrane.
    - reference_id: PMID:9495346
      supporting_text: >-
        Tim10 and Tim12 are found in a complex with Tim22, which takes over the precursor
        and mediates its membrane-potential-dependent insertion into the inner membrane.
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      TIM10 participates in the overall process of protein insertion into the
      mitochondrial inner membrane. While TIM10 itself does not perform the insertion
      step (that is Tim22), it is an essential component of the pathway that
      chaperones precursors across the IMS to the TIM22 insertase. Multiple studies
      have shown that loss of TIM10 function blocks carrier protein import and
      insertion (PMID:9430585, PMID:9495346, PMID:11483513).
    action: ACCEPT
    reason: >-
      This biological process annotation is appropriate. TIM10 is directly involved in
      the protein insertion pathway even though it functions at the chaperoning step
      rather than the insertion step per se. The IBA annotation is well supported by
      extensive experimental evidence across multiple publications showing TIM10 is
      essential for this process.
    supported_by:
    - reference_id: PMID:9430585
      supporting_text: >-
        Tim10p and Tim12p, were shown to mediate import of multispanning carriers into
        the inner membrane.
    - reference_id: PMID:11483513
      supporting_text: >-
        The reconstituted TIM10 complex not only facilitated passage of AAC across the
        outer membrane but also ensured its accurate membrane insertion.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      TIM10 is associated with the mitochondrial inner membrane as a peripheral
      membrane protein on the intermembrane space side. UniProt annotates TIM10
      to the mitochondrion inner membrane as a peripheral membrane protein on
      the intermembrane side. This IEA annotation based on UniProt subcellular
      location mapping is supported by experimental data (PMID:10648604).
    action: ACCEPT
    reason: >-
      TIM10 is indeed associated with the mitochondrial inner membrane as part of the
      300 kDa TIM22 complex. A fraction of TIM10 is peripherally associated with the
      inner membrane via its interaction with TIM12/TIM22. The IEA is consistent
      with the IDA annotation to the same term (PMID:10648604).
    supported_by:
    - reference_id: PMID:10648604
      supporting_text: >-
        The TIM22 complex contains the peripheral subunits Tim9p, Tim10p, and Tim12p
        and the integral membrane subunits Tim22p and Tim54p.
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      TIM10 is a soluble protein of the mitochondrial intermembrane space. This
      IEA annotation from UniProt subcellular location mapping is well supported by
      multiple experimental studies showing TIM10 resides in the IMS as part of the
      soluble 70 kDa TIM9-TIM10 complex (PMID:9889188, PMID:9822593).
    action: ACCEPT
    reason: >-
      The mitochondrial IMS is the primary location of TIM10. The bulk of TIM10 exists
      as a soluble hexameric complex with TIM9 in the IMS. This is one of the most
      well-established features of TIM10 biology.
    supported_by:
    - reference_id: PMID:9889188
      supporting_text: >-
        Tim9 is located in the mitochondrial intermembrane space and is organized into
        two distinct hetero-oligomeric assemblies with Tim10 and Tim12.
- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      TIM10 is involved in protein transport, specifically transporting mitochondrial
      carrier proteins from the TOM complex across the IMS to the TIM22 complex.
      This IEA from UniProt keyword mapping is correct but overly general compared
      to the more specific GO:0045039 (protein insertion into mitochondrial inner
      membrane) annotations already present.
    action: ACCEPT
    reason: >-
      While this is a very broad term, it is not incorrect. TIM10 is fundamentally a
      protein transporter in the IMS. The IEA is acceptable as a broader classification
      that complements the more specific annotations to GO:0045039.
    supported_by:
    - reference_id: PMID:9430585
      supporting_text: >-
        Tim10p and Tim12p, were shown to mediate import of multispanning carriers into
        the inner membrane.
- term:
    id: GO:0042719
    label: mitochondrial intermembrane space chaperone complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      TIM10 is a core component of the mitochondrial intermembrane space chaperone
      complex (the TIM9-TIM10 complex). This IEA from ARBA is well supported by
      multiple experimental IDA annotations to the same term (PMID:9822593,
      PMID:9889188).
    action: ACCEPT
    reason: >-
      This IEA annotation is fully consistent with the experimentally determined
      localization of TIM10 as a subunit of the TIM9-TIM10 IMS chaperone complex.
    supported_by:
    - reference_id: PMID:9822593
      supporting_text: >-
        Most of Tim9p is associated with Tim10p in a soluble 70 kDa complex.
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      TIM10 is involved in the process of protein insertion into the mitochondrial
      inner membrane. This IEA from ARBA is consistent with multiple experimental
      IDA and IMP annotations to the same term (PMID:9430585, PMID:9495346,
      PMID:10648604, PMID:19037098).
    action: ACCEPT
    reason: >-
      This IEA annotation correctly reflects TIM10 involvement in inner membrane
      protein insertion. It is redundant with the experimentally supported annotations
      to the same term, but acceptable as an independent IEA inference.
    supported_by:
    - reference_id: PMID:9430585
      supporting_text: >-
        Tim10p and Tim12p, were shown to mediate import of multispanning carriers into
        the inner membrane.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      TIM10 contains a twin CX3C zinc-finger-like motif with four conserved cysteines
      that can bind zinc. However, zinc binding occurs specifically during cytoplasmic
      transit to stabilize the reduced form and facilitate import into mitochondria.
      In the mitochondrial IMS, the mature protein forms disulfide bonds rather than
      coordinating zinc (PMID:9495346, UniProt). The IEA from UniProt keyword mapping
      to the general metal ion binding term is acceptable but the zinc binding is
      transient and context-dependent.
    action: ACCEPT
    reason: >-
      TIM10 does bind metal ions (specifically zinc) via its CX3C motifs, though this
      occurs in the cytoplasm rather than in its functional IMS location. The IEA
      annotation to this general term is not wrong, and the more specific zinc ion
      binding annotation (GO:0008270) provides better specificity.
    supported_by:
    - reference_id: PMID:9495346
      supporting_text: >-
        Both proteins contain a zinc-finger-like motif with four cysteines and bind
        equimolar amounts of zinc ions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11483513
  review:
    summary: >-
      This annotation records the physical interaction of TIM10 with TIM9 (O74700)
      as detected in PMID:11483513. Luciano et al. showed that Tim9 and Tim10 purified
      from E. coli can form a complex of the same size as the endogenous complex.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding (GO:0005515) is uninformative and should
      be replaced by more specific molecular function terms. The interaction between
      TIM10 and TIM9 is captured by the complex membership annotations (GO:0042719
      and GO:0042721) and by the more informative unfolded protein carrier activity
      (GO:0140309) proposed as a replacement for GO:0051082.
    supported_by:
    - reference_id: PMID:11483513
      supporting_text: >-
        Tim9 and Tim10 purified from Escherichia coli can form a complex of the same
        size as the endogenous complex from yeast mitochondria.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12637749
  review:
    summary: >-
      This annotation records the physical interaction of TIM10 with TIM18 (Q08749)
      as detected in PMID:12637749. Rehling et al. identified TIM10 as part of the
      TIM22 complex which includes TIM18.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction of TIM10 with TIM18 is better
      captured by the annotation to TIM22 complex membership (GO:0042721).
    supported_by:
    - reference_id: PMID:12637749
      supporting_text: >-
        Protein insertion into the mitochondrial inner membrane by a twin-pore translocase.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17882259
  review:
    summary: >-
      This annotation records a physical interaction between TIM10 and TIM18 (Q08749)
      from PMID:17882259 (Shy1 couples Cox1 translational regulation to cytochrome c
      oxidase assembly). This is a large-scale interaction study.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. This interaction is better captured by the
      complex membership annotations. The specific paper is about Shy1/Cox1 regulation
      and TIM10 interaction data from it is likely from a proteomics/interactomics
      dataset.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23267104
  review:
    summary: >-
      This annotation records a physical interaction of TIM10 with TIM12 (P32830)
      from PMID:23267104 (proteome-wide protein interaction measurements of bacterial
      proteins of unknown function). This appears to be a cross-species or
      high-throughput interaction study.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The TIM10-TIM12 interaction is well
      established and captured by the complex membership annotations (GO:0042721,
      GO:0042719). There is no need for a separate generic protein binding annotation.
    supported_by:
    - reference_id: PMID:9822593
      supporting_text: >-
        A small fraction of Tim9p is bound to the outer face of the inner membrane in a
        300 kDa complex whose other subunits include Tim54p, Tim22p, Tim12p and Tim10p.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107014
  review:
    summary: >-
      This annotation records a physical interaction of TIM10 with human MAGEA2B
      (P43356) from PMID:27107014 (an inter-species protein-protein interaction
      network). This is a cross-species interaction that likely has no physiological
      relevance for yeast TIM10 function.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Furthermore, this cross-species interaction
      with human MAGEA2B has no known physiological relevance for yeast TIM10 and
      likely reflects in vitro assay artifacts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107014
  review:
    summary: >-
      This annotation records a physical interaction of TIM10 with human TEX11
      (Q8IYF3-3) from PMID:27107014 (an inter-species protein-protein interaction
      network). This is a cross-species interaction that likely has no physiological
      relevance for yeast TIM10 function.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Furthermore, this cross-species interaction
      with human TEX11 has no known physiological relevance for yeast TIM10 and
      likely reflects in vitro assay artifacts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9495346
  review:
    summary: >-
      This annotation records a physical interaction of TIM10 with TIM12 (P32830)
      from PMID:9495346. Sirrenberg et al. showed Tim10 and Tim12 interact
      sequentially with carrier precursors and form a complex with Tim22.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The TIM10-TIM12 interaction is better
      represented by the complex membership annotations (GO:0042721, GO:0042719).
      The more informative molecular function is protein transporter activity
      (GO:0140318) or unfolded protein carrier activity (GO:0140309).
    supported_by:
    - reference_id: PMID:9495346
      supporting_text: >-
        Tim10 and Tim12 are found in a complex with Tim22, which takes over the precursor
        and mediates its membrane-potential-dependent insertion into the inner membrane.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:9889188
  review:
    summary: >-
      TIM10 localizes to mitochondria. Adam et al. (PMID:9889188) identified Tim9
      as a mitochondrial intermembrane space component organized with Tim10 and Tim12,
      confirming mitochondrial localization of TIM10 by direct assay.
    action: ACCEPT
    reason: >-
      TIM10 is a well-established mitochondrial protein. The IDA annotation is
      well supported, though GO:0005758 (mitochondrial intermembrane space) is more
      specific.
    supported_by:
    - reference_id: PMID:9889188
      supporting_text: >-
        Tim9 is located in the mitochondrial intermembrane space and is organized into
        two distinct hetero-oligomeric assemblies with Tim10 and Tim12.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:10648604
  review:
    summary: >-
      TIM10 is a peripheral membrane protein associated with the inner membrane as
      part of the TIM22 complex. Koehler et al. (PMID:10648604) showed the TIM22
      complex contains peripheral subunits Tim9p, Tim10p, and Tim12p and integral
      membrane subunits Tim22p and Tim54p.
    action: ACCEPT
    reason: >-
      TIM10 is peripherally associated with the mitochondrial inner membrane via its
      interaction with the TIM22 complex. This IDA annotation is experimentally well
      supported.
    supported_by:
    - reference_id: PMID:10648604
      supporting_text: >-
        The TIM22 complex contains the peripheral subunits Tim9p, Tim10p, and Tim12p
        and the integral membrane subunits Tim22p and Tim54p.
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IDA
  original_reference_id: PMID:19037698
  review:
    summary: >-
      This annotation cites PMID:19037698, which is about "The Dutch multicenter
      experience of the endo-sponge treatment for anastomotic leakage after colorectal
      surgery" and has nothing to do with TIM10 or mitochondria. This is clearly
      a PMID error in the ComplexPortal annotation source. The intended reference was
      likely PMID:19037098 (Baker et al. 2009, about the Tim9-Tim10 complex structure)
      or another mitochondrial study. Despite the wrong reference, TIM10 IMS
      localization is well established.
    action: ACCEPT
    reason: >-
      The annotation to GO:0005758 (mitochondrial intermembrane space) is correct
      for TIM10 -- it is one of the best-characterized IMS proteins. However, the
      cited PMID:19037698 is clearly wrong (it is an unrelated colorectal surgery
      paper). This is likely a PMID transcription error; the correct reference is
      probably PMID:19037098 (Baker et al. 2009, Mol Biol Cell). The localization
      itself is supported by multiple other references (PMID:9889188, PMID:9822593).
    additional_reference_ids:
    - PMID:19037098
    - PMID:9889188
    supported_by:
    - reference_id: PMID:9889188
      supporting_text: >-
        Tim9 is located in the mitochondrial intermembrane space and is organized into
        two distinct hetero-oligomeric assemblies with Tim10 and Tim12.
    - reference_id: PMID:19037098
      supporting_text: >-
        The Tim9-Tim10 complex plays an essential role in mitochondrial protein import
        by chaperoning select hydrophobic precursor proteins across the intermembrane space.
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:10648604
  review:
    summary: >-
      Koehler et al. (PMID:10648604) showed that TIM10 is part of the TIM22 complex
      that mediates insertion of imported proteins into the yeast mitochondrial inner
      membrane. Tim18p deletion impaired import and was synthetically lethal with
      Tim10p temperature-sensitive mutations, establishing TIM10 involvement in the
      insertion pathway.
    action: ACCEPT
    reason: >-
      TIM10 is an essential component of the carrier protein import and inner membrane
      insertion pathway. This IDA annotation is well supported by the cited reference
      and multiple other publications.
    supported_by:
    - reference_id: PMID:10648604
      supporting_text: >-
        Deletion of Tim18p decreases the growth rate of yeast cells by a factor of two
        and is synthetically lethal with temperature-sensitive mutations in Tim9p or Tim10p.
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:19037098
  review:
    summary: >-
      Baker et al. (PMID:19037098) determined the structure of the yeast Tim9-Tim10
      hexameric assembly at 2.5 A and performed mutational analysis showing that
      disruption of the complex causes defective import of precursor substrates.
    action: ACCEPT
    reason: >-
      This IDA annotation from Baker et al. is well supported. The study demonstrated
      that mutations destabilizing the Tim9-Tim10 complex cause defective import of
      precursor substrates, directly confirming TIM10 involvement in the process.
    supported_by:
    - reference_id: PMID:19037098
      supporting_text: >-
        Mutation of these residues destabilizes the complex, causes defective import of
        precursor substrates, and results in yeast growth defects.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-SCE-9839836
  review:
    summary: >-
      This Reactome annotation refers to the reaction "YME1 degrades TIM10",
      indicating TIM10 is located at the mitochondrial inner membrane where it can
      be degraded by the i-AAA protease YME1. TIM10 association with the inner
      membrane is well established.
    action: ACCEPT
    reason: >-
      TIM10 is peripherally associated with the mitochondrial inner membrane as part
      of the TIM22 complex. The Reactome TAS annotation is consistent with the IDA
      annotation to the same term.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: RCA
  original_reference_id: PMID:30358795
  review:
    summary: >-
      TIM10 contains a twin CX3C motif that can coordinate zinc ions. However, zinc
      binding is context-dependent: TIM10 binds zinc in the cytoplasm (in its reduced
      form before import), but in the mitochondrial IMS the cysteines form disulfide
      bonds rather than coordinating zinc (PMID:9495346, UniProt). The RCA annotation
      from a zinc proteome study (PMID:30358795) is acceptable but should be
      understood in context.
    action: ACCEPT
    reason: >-
      TIM10 does bind zinc via its CX3C motifs, though this occurs in the cytoplasmic
      reduced state rather than in the functional IMS oxidized state. The annotation
      is not incorrect -- TIM10 is part of the zinc proteome -- but the zinc binding
      is transient and occurs during biogenesis rather than function.
    supported_by:
    - reference_id: PMID:9495346
      supporting_text: >-
        Both proteins contain a zinc-finger-like motif with four cysteines and bind
        equimolar amounts of zinc ions.
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: TAS
  original_reference_id: Reactome:R-SCE-1252259
  review:
    summary: >-
      This Reactome annotation references the reaction "TIM9:TIM10 binds hydrophobic
      proteins" in the IMS. This is consistent with the known function of the
      TIM9-TIM10 complex as a soluble IMS chaperone.
    action: ACCEPT
    reason: >-
      TIM10 resides in the mitochondrial IMS as part of the soluble TIM9-TIM10
      complex. The Reactome TAS annotation is consistent with multiple experimental
      annotations to the same term.
    supported_by:
    - reference_id: PMID:9889188
      supporting_text: >-
        Tim9 is located in the mitochondrial intermembrane space and is organized into
        two distinct hetero-oligomeric assemblies with Tim10 and Tim12.
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: TAS
  original_reference_id: Reactome:R-SCE-1252260
  review:
    summary: >-
      This Reactome annotation references the reaction "MIA40:ERV1 oxidizes cysteine
      residues to cystine disulfide bonds", referring to the Mia40/Erv1 disulfide
      relay pathway that imports and oxidizes small TIM proteins like TIM10 in the
      IMS.
    action: ACCEPT
    reason: >-
      TIM10 is a substrate of the Mia40/Erv1 disulfide relay system in the IMS.
      The annotation correctly places TIM10 in the IMS where it undergoes oxidative
      folding.
- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IMP
  original_reference_id: PMID:9430585
  review:
    summary: >-
      Koehler et al. (PMID:9430585) demonstrated that Tim10p is essential for
      transport of carrier precursors across the outer membrane. Using temperature-
      sensitive mutants, they showed Tim10p mediates import of multispanning carriers.
      GO:0140318 (protein transporter activity) is defined as directly binding to a
      specific protein and delivering it to a specific cellular location.
    action: ACCEPT
    reason: >-
      TIM10 directly binds carrier protein precursors and delivers them from the TOM
      complex to the TIM22 complex. This is precisely what protein transporter activity
      describes. The IMP evidence from temperature-sensitive mutant analysis is robust.
    supported_by:
    - reference_id: PMID:9430585
      supporting_text: "Tim10p readily dissociated from the complex and was required to transport carrier precursors across the outer membrane; Tim12p was firmly bound to Tim22p and mediated the insertion of carriers into the inner membrane."
- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IDA
  original_reference_id: PMID:9495346
  review:
    summary: >-
      Sirrenberg et al. (PMID:9495346) showed Tim10 interacts with carrier protein
      precursors and facilitates their translocation across the outer membrane. Tim10
      and Tim12 interact sequentially with precursors and deliver them to Tim22 for
      insertion.
    action: ACCEPT
    reason: >-
      This IDA annotation is well supported. TIM10 directly binds to and transports
      carrier protein precursors through the IMS, which is the core definition of
      protein transporter activity.
    supported_by:
    - reference_id: PMID:9495346
      supporting_text: >-
        Two related proteins in the intermembrane space, Tim10/Mrs11 and Tim12/Mrs5,
        interact sequentially with these precursors and facilitate their translocation
        across the outer membrane, irrespective of the membrane potential.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:24769239
  review:
    summary: >-
      This HDA annotation from a large-scale quantitative mitochondrial proteomics
      study (PMID:24769239) confirms TIM10 as a mitochondrial protein. High-throughput
      direct assay evidence.
    action: ACCEPT
    reason: >-
      TIM10 mitochondrial localization is well established. This HDA annotation from
      a mitochondrial proteome analysis is consistent with all other localization data.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:16823961
  review:
    summary: >-
      This HDA annotation from a yeast mitochondrial proteomics study (PMID:16823961)
      by Reinders et al. confirms TIM10 as a mitochondrial protein identified by mass
      spectrometry.
    action: ACCEPT
    reason: >-
      TIM10 mitochondrial localization is well established. This HDA annotation from
      a mitochondrial proteome analysis provides independent proteomics confirmation.
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IMP
  original_reference_id: PMID:9430585
  review:
    summary: >-
      Koehler et al. (PMID:9430585) used temperature-sensitive Tim10p mutants
      to show that Tim10p is required for import of multispanning carrier proteins
      into the inner membrane.
    action: ACCEPT
    reason: >-
      This IMP annotation is well supported by the temperature-sensitive mutant
      phenotype analysis. Loss of Tim10p function blocks carrier protein insertion
      into the inner membrane.
    supported_by:
    - reference_id: PMID:9430585
      supporting_text: >-
        Tim10p and Tim12p, were shown to mediate import of multispanning carriers into
        the inner membrane.
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:9495346
  review:
    summary: >-
      Sirrenberg et al. (PMID:9495346) demonstrated Tim10 is involved in the pathway
      for carrier protein insertion into the inner membrane, working with Tim12 and
      Tim22 to facilitate translocation and insertion.
    action: ACCEPT
    reason: >-
      This IDA annotation is well supported. TIM10 is essential for the carrier protein
      import and inner membrane insertion pathway.
    supported_by:
    - reference_id: PMID:9495346
      supporting_text: "Two related proteins in the intermembrane space, Tim10/Mrs11 and Tim12/Mrs5, interact sequentially with these precursors and facilitate their translocation across the outer membrane, irrespective of the membrane potential."
- term:
    id: GO:0042719
    label: mitochondrial intermembrane space chaperone complex
  evidence_type: IDA
  original_reference_id: PMID:9822593
  review:
    summary: >-
      Koehler et al. (PMID:9822593) showed that Tim9p and Tim10p co-purify in
      successive chromatographic fractionations and co-immunoprecipitate, forming
      the soluble 70 kDa IMS chaperone complex.
    action: ACCEPT
    reason: >-
      This is one of the defining experimental demonstrations that TIM10 is a core
      subunit of the IMS chaperone complex. The IDA evidence is robust.
    supported_by:
    - reference_id: PMID:9822593
      supporting_text: >-
        Most of Tim9p is associated with Tim10p in a soluble 70 kDa complex. Tim9p and
        Tim10p co-purify in successive chromatographic fractionations and
        co-immunoprecipitated with each other.
- term:
    id: GO:0042719
    label: mitochondrial intermembrane space chaperone complex
  evidence_type: IDA
  original_reference_id: PMID:9889188
  review:
    summary: >-
      Adam et al. (PMID:9889188) identified Tim9 as a new component of the TIM22.54
      translocase and showed it forms two distinct hetero-oligomeric assemblies with
      Tim10 and Tim12 in the IMS.
    action: ACCEPT
    reason: >-
      This IDA annotation is well supported. The study demonstrated that TIM10
      is organized into the TIM9-TIM10 complex in the IMS.
    supported_by:
    - reference_id: PMID:9889188
      supporting_text: >-
        Tim9 is located in the mitochondrial intermembrane space and is organized into
        two distinct hetero-oligomeric assemblies with Tim10 and Tim12.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:12138093
  review:
    summary: >-
      Vial et al. (PMID:12138093) demonstrated that the reconstituted TIM10 complex
      binds to the physiological substrate ADP/ATP carrier and displays chaperone
      activity in refolding model substrate firefly luciferase. While TIM10 does bind
      unfolded proteins, the term GO:0051082 (unfolded protein binding) fails to
      capture the critical carrier/escort function of TIM10. TIM10 does not merely
      bind unfolded proteins -- it actively escorts them across the aqueous IMS from
      the TOM complex to the TIM22 complex, functioning as a true protein carrier
      chaperone. GO:0140309 (unfolded protein carrier activity) is defined as "A
      protein carrier activity that binds to a protein in an unfolded state and
      escorts it between two different cellular components. The unfolded protein
      carrier prevents aggregation of the target protein." This precisely describes
      TIM10 function.
    action: MODIFY
    reason: >-
      GO:0051082 (unfolded protein binding) is too generic and misses the essential
      carrier/escort function of TIM10. The TIM9-TIM10 complex is a quintessential
      unfolded protein carrier: it binds hydrophobic unfolded precursors in the IMS,
      prevents their aggregation, and escorts them between two cellular compartments
      (from the TOM complex at the outer membrane to the TIM22 complex at the inner
      membrane). GO:0140309 (unfolded protein carrier activity) captures this complete
      function. The reconstituted complex not only bound substrate but also "facilitated
      passage of AAC across the outer membrane" and "ensured its accurate membrane
      insertion" (PMID:11483513), confirming active escort rather than passive binding.
    proposed_replacement_terms:
    - id: GO:0140309
      label: unfolded protein carrier activity
    supported_by:
    - reference_id: PMID:12138093
      supporting_text: >-
        the reconstituted TIM10 complex is functional because it bound to the
        physiological substrate ADP/ATP carrier and displayed chaperone activity in
        refolding the model substrate firefly luciferase.
    - reference_id: PMID:11483513
      supporting_text: >-
        The reconstituted TIM10 complex not only facilitated passage of AAC across the
        outer membrane but also ensured its accurate membrane insertion.
    - reference_id: PMID:9430585
      supporting_text: >-
        Both proteins may function as intermembrane space chaperones for the highly
        insoluble carrier proteins.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:10648604
  title: Tim18p, a new subunit of the TIM22 complex that mediates insertion of imported
    proteins into the yeast mitochondrial inner membrane.
  findings:
  - statement: >-
      TIM22 complex contains peripheral subunits Tim9p, Tim10p, Tim12p and integral
      membrane subunits Tim22p, Tim54p, and Tim18p. Tim18p deletion is synthetically
      lethal with Tim10p temperature-sensitive mutations.
    supporting_text: "The TIM22 complex contains the peripheral subunits Tim9p, Tim10p, and Tim12p and the integral membrane subunits Tim22p and Tim54p."
- id: PMID:11483513
  title: Functional reconstitution of the import of the yeast ADP/ATP carrier mediated
    by the TIM10 complex.
  findings:
  - statement: >-
      Tim9 and Tim10 purified from E. coli form a complex identical to the endogenous
      mitochondrial TIM10 complex. The reconstituted complex restores AAC import in
      TIM10-deficient mitochondria, facilitating passage across the outer membrane and
      accurate inner membrane insertion.
    supporting_text: "The reconstituted TIM10 complex not only facilitated passage of AAC across the outer membrane but also ensured its accurate membrane insertion."
- id: PMID:12138093
  title: Assembly of Tim9 and Tim10 into a functional chaperone.
  findings:
  - statement: >-
      Tim9 and Tim10 self-associate and assemble into a stable hexameric complex with
      submicromolar affinity. The reconstituted TIM10 complex binds the ADP/ATP carrier
      substrate and displays chaperone activity for luciferase refolding. Hexameric
      assembly is necessary for chaperone function.
    supporting_text: "the reconstituted TIM10 complex is functional because it bound to the physiological substrate ADP/ATP carrier and displayed chaperone activity in refolding the model substrate firefly luciferase."
- id: PMID:12637749
  title: Protein insertion into the mitochondrial inner membrane by a twin-pore translocase.
  findings:
  - statement: >-
      The TIM22 complex functions as a twin-pore translocase for carrier protein
      insertion. TIM10 is identified as a component of this complex.
    supporting_text: "We purified the protein insertion complex (TIM22 complex), a twin-pore translocase that mediated the insertion of precursor proteins in a three-step process."
- id: PMID:16823961
  title: 'Toward the complete yeast mitochondrial proteome: multidimensional separation
    techniques for mitochondrial proteomics.'
  findings:
  - statement: >-
      TIM10 identified as a mitochondrial protein by mass spectrometry in a comprehensive
      yeast mitochondrial proteome analysis.
    supporting_text: "A total of 851 different proteins (PROMITO dataset) were identified by use of multidimensional LC-MS/MS"
- id: PMID:17882259
  title: Shy1 couples Cox1 translational regulation to cytochrome c oxidase assembly.
  findings: []
- id: PMID:19037098
  title: Structural and functional requirements for activity of the Tim9-Tim10 complex
    in mitochondrial protein import.
  findings:
  - statement: >-
      Crystal structure of the Tim9-Tim10 hexamer at 2.5 A resolution. Each subunit
      has a central loop flanked by disulfide bonds with N- and C-terminal tentacle-like
      helices. Conserved salt bridges connect alternating subunits. Tim9 N-terminal
      region is required for efficient substrate trapping.
    supporting_text: "we report the structure of the yeast Tim9-Tim10 hexameric assembly determined to 2.5 A and have performed mutational analysis in yeast to evaluate the specific roles of Tim9 and Tim10."
- id: PMID:19037698
  title: The Dutch multicenter experience of the endo-sponge treatment for anastomotic
    leakage after colorectal surgery.
  is_invalid: true
  findings:
  - statement: >-
      This publication is about colorectal surgery and has no relevance to TIM10 or
      mitochondria. It was likely cited by error in ComplexPortal (possibly confused
      with PMID:19037098).
    supporting_text: "Anastomotic leakage is a feared complication following colorectal surgery [this paper has no relevance to TIM10]"
- id: PMID:23267104
  title: Proteome-wide protein interaction measurements of bacterial proteins of unknown
    function.
  findings: []
- id: PMID:24769239
  title: Quantitative variations of the mitochondrial proteome and phosphoproteome
    during fermentative and respiratory growth in Saccharomyces cerevisiae.
  findings:
  - statement: >-
      TIM10 identified as a mitochondrial protein in a quantitative proteomics study.
    supporting_text: "we performed an overall quantitative proteomic and phosphoproteomic study of isolated mitochondria extracted from yeast grown on fermentative (glucose or galactose) and respiratory (lactate) media."
- id: PMID:27107014
  title: An inter-species protein-protein interaction network across vast evolutionary
    distance.
  findings: []
- id: PMID:30358795
  title: The cellular economy of the Saccharomyces cerevisiae zinc proteome.
  findings:
  - statement: >-
      TIM10 identified as part of the yeast zinc proteome based on its CX3C
      zinc-binding motifs.
    supporting_text: "The yeast zinc proteome of 582 known or potential zinc-binding proteins was identified using a bioinformatics analysis that combined global domain searches with local motif searches."
- id: PMID:9430585
  title: Import of mitochondrial carriers mediated by essential proteins of the intermembrane
    space.
  findings:
  - statement: >-
      Tim10p and Tim12p are essential IMS proteins that mediate import of multispanning
      carrier proteins into the inner membrane. Tim10p is required for transport across
      the outer membrane; Tim12p mediates insertion. Both may function as IMS chaperones.
    supporting_text: "Both proteins may function as intermembrane space chaperones for the highly insoluble carrier proteins."
- id: PMID:9495346
  title: Carrier protein import into mitochondria mediated by the intermembrane proteins
    Tim10/Mrs11 and Tim12/Mrs5.
  findings:
  - statement: >-
      Tim10/Mrs11 and Tim12/Mrs5 interact sequentially with carrier precursors in the
      IMS and facilitate their translocation. Tim10 and Tim12 form a complex with Tim22.
      Both contain zinc-finger-like CX3C motifs that bind zinc.
    supporting_text: "Both proteins contain a zinc-finger-like motif with four cysteines and bind equimolar amounts of zinc ions."
- id: PMID:9822593
  title: Tim9p, an essential partner subunit of Tim10p for the import of mitochondrial
    carrier proteins.
  findings:
  - statement: >-
      Tim9p is an essential partner of Tim10p. Most Tim9p is in a soluble 70 kDa complex
      with Tim10p. A small fraction is in a 300 kDa inner membrane complex with Tim54p,
      Tim22p, Tim12p, and Tim10p. Tim9p is a new subunit of the TIM machinery that
      guides hydrophobic inner membrane proteins across the aqueous IMS.
    supporting_text: "Most of Tim9p is associated with Tim10p in a soluble 70 kDa complex."
- id: PMID:9889188
  title: Tim9, a new component of the TIM22.54 translocase in mitochondria.
  findings:
  - statement: >-
      Tim9 is an essential IMS protein organized into two hetero-oligomeric assemblies
      with Tim10 and Tim12. The TIM9.10 complex mediates partial translocation of
      carriers across the outer membrane. The TIM9.10.12 complex assists further
      translocation in association with TIM22.54.
    supporting_text: "Tim9 is located in the mitochondrial intermembrane space and is organized into two distinct hetero-oligomeric assemblies with Tim10 and Tim12."
- id: Reactome:R-SCE-1252259
  title: TIM9:TIM10 binds hydrophobic proteins
  findings: []
- id: Reactome:R-SCE-1252260
  title: MIA40:ERV1 oxidizes cysteine residues to cystine disulfide bonds
  findings: []
- id: Reactome:R-SCE-9839836
  title: YME1 degrades TIM10
  findings: []
core_functions:
- description: >-
    TIM10 functions as an unfolded protein carrier in the mitochondrial intermembrane
    space (IMS). As part of the hexameric TIM9-TIM10 chaperone complex, it binds
    hydrophobic unfolded precursor proteins (primarily mitochondrial carrier family
    members) exiting the TOM translocase and escorts them across the aqueous IMS to
    the TIM22 insertase complex at the inner membrane. TIM10 acts as a substrate
    sensor within the complex. This is an ATP-independent holdase/carrier function
    that prevents aggregation of highly hydrophobic transmembrane precursors.
  molecular_function:
    id: GO:0140309
    label: unfolded protein carrier activity
  directly_involved_in:
  - id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  locations:
  - id: GO:0005758
    label: mitochondrial intermembrane space
  in_complex:
    id: GO:0042719
    label: mitochondrial intermembrane space chaperone complex
  supported_by:
  - reference_id: PMID:12138093
    supporting_text: >-
      the reconstituted TIM10 complex is functional because it bound to the
      physiological substrate ADP/ATP carrier and displayed chaperone activity in
      refolding the model substrate firefly luciferase.
  - reference_id: PMID:9430585
    supporting_text: >-
      Both proteins may function as intermembrane space chaperones for the highly
      insoluble carrier proteins.
  - reference_id: PMID:11483513
    supporting_text: >-
      The reconstituted TIM10 complex not only facilitated passage of AAC across the
      outer membrane but also ensured its accurate membrane insertion.
- description: >-
    TIM10 has protein transporter activity, directly binding to and delivering
    mitochondrial carrier protein precursors from the TOM complex to the TIM22
    complex. This transporter function overlaps with but is distinct from the unfolded
    protein carrier activity, emphasizing the directed delivery aspect of TIM10 function.
  molecular_function:
    id: GO:0140318
    label: protein transporter activity
  directly_involved_in:
  - id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  locations:
  - id: GO:0005758
    label: mitochondrial intermembrane space
  in_complex:
    id: GO:0042719
    label: mitochondrial intermembrane space chaperone complex
  supported_by:
  - reference_id: PMID:9430585
    supporting_text: >-
      Tim10p readily dissociated from the complex and was required to transport carrier
      precursors across the outer membrane.
  - reference_id: PMID:9495346
    supporting_text: >-
      Two related proteins in the intermembrane space, Tim10/Mrs11 and Tim12/Mrs5,
      interact sequentially with these precursors and facilitate their translocation
      across the outer membrane, irrespective of the membrane potential.