TIM22 is the essential core channel-forming subunit of the TIM22 complex in the mitochondrial inner membrane. It forms a voltage-activated, signal-gated twin-pore translocase that mediates the insertion of multi-pass transmembrane proteins into the inner membrane. Cryo-EM of the endogenous yeast TIM22 complex at 3.8 angstrom resolution (Zhang et al. 2021, doi:10.1038/s41422-020-00399-0) revealed a 7-subunit architecture (Tim22, Tim54, Tim18, Sdh3, Tim9, Tim10, Tim12) with Tim22 possessing 4 transmembrane helices, a C42-C141 disulfide bond between TM1 and TM2, and conserved charged residues (E140, D190, K127, K169) critical for function -- single mutants such as E140A or K127A severely impair growth. The hexameric small-Tim chaperone ring (Tim9/Tim10/Tim12) sits tilted approximately 45 degrees relative to the membrane plane. Notably, the cryo-EM structure did not reveal a clear open translocation pore in the captured state, fueling debate about whether TIM22 operates via conformationally gated pore formation in distinct functional states or via an insertase-like mechanism that lowers the energetic barrier for helix insertion by altering local bilayer properties. Canonical TIM22 substrates are 6-TM metabolite carriers (e.g., Aac2/Pet9 ADP/ATP carrier, Pic/Pic2 phosphate carrier, Dic1 dicarboxylate carrier), but the substrate spectrum extends to non-canonical cargos including 4-TM translocase subunits (Tim17, Tim22, Tim23) and mitochondrial pyruvate carrier (MPC) subunits with fewer transmembrane segments. TIM22 recognizes internal targeting signals (not N-terminal presequences) and uses the membrane potential (Delta-psi) as external driving force. It is distinct from the TIM23 complex, which imports presequence-containing matrix proteins. Recent work has revealed functional crosstalk between the TIM22 complex and the Yme1 i-AAA protease quality control machinery: Yme1 is required for stability of the TIM22 complex and for proteostasis of TIM22 pathway substrates, with a small transient pool of Yme1 associating with TIM22 (Kumar et al. 2023, doi:10.1242/jcs.260060). Loss of Yme1 leads to accumulation of TIM22 substrates outside mitochondria and compromised respiration. Substrate delivery to the TIM22 complex is performed by the small TIM chaperones (Tim9-Tim10, Tim8-Tim13) in the intermembrane space.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030943 mitochondrion targeting sequence binding | IBA GO_REF:0000033 | MODIFY | Summary: IBA annotation for mitochondrion targeting sequence binding. TIM22 does bind targeting signals, but specifically internal targeting signals of carrier proteins, not the classical N-terminal matrix targeting presequences. The term GO:0030943 is defined broadly as "Binding to a mitochondrion targeting sequence, a specific peptide sequence that acts as a signal to localize the protein within the mitochondrion" -- this is broad enough to encompass internal targeting signals. Kovermann et al. (PMID:11864609) demonstrated that reconstituted Tim22 forms a channel that "specifically responds to an internal targeting signal, but not to presequences." The IBA annotation is phylogenetically sound and the term is acceptable, though imprecise about the type of targeting signal recognized. Reason: GO:0030943 (mitochondrion targeting sequence binding) is obsolete in the current GO release (consider GO:0140436 / GO:0008320). Tim22 is the internal-signal-gated carrier translocase channel rather than a targeting-signal receptor; its signal response is part of its protein-conducting channel activity, captured by GO:0008320 rather than the receptor MF GO:0140436. TIM22 already carries GO:0008320 (IBA and IDA), so this MODIFY folds the row into that existing annotation and asserts nothing new. The underlying observation stands: TIM22 recognizes internal targeting signals of carrier proteins (PMID:11864609), and the IBA is phylogenetically sound for the TIM22 channel function. Proposed replacements: transmembrane protein transporter activity Supporting Evidence: PMID:11864609 The channel is voltage-activated and specifically responds to an internal targeting signal, but not to presequences |
| GO:0042721 TIM22 mitochondrial import inner membrane insertion complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for TIM22 complex membership. TIM22 is the essential core channel subunit of the TIM22 complex. Multiple studies confirm this: Kerscher et al. (PMID:10637294) and Koehler et al. (PMID:10648604) identified TIM22 as a core integral membrane subunit, and Rehling et al. (PMID:12637749) showed it forms the twin-pore translocase. UniProt describes it as "Essential core component of the TIM22 complex." Reason: TIM22 is the defining, essential core subunit of the TIM22 complex. This is one of the most well-established annotations for this gene, supported by extensive experimental evidence (PMID:10637294, PMID:10648604, PMID:12637749) and phylogenetically sound. Supporting Evidence: PMID:10637294 Tim18p is a new component of the Tim54p-Tim22p translocon in the mitochondrial inner membrane PMID:10648604 The TIM22 complex contains the peripheral subunits Tim9p, Tim10p, and Tim12p and the integral membrane subunits Tim22p and Tim54p |
| GO:0045039 protein insertion into mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for protein insertion into mitochondrial inner membrane. This is the core biological process of TIM22. Sirrenberg et al. (PMID:8955274) first showed that "Tim22 is required for the import of proteins of the mitochondrial ADP/ATP carrier (AAC) family into the inner membrane." Kovermann et al. (PMID:11864609) demonstrated TIM22 forms the channel, and Rehling et al. (PMID:12637749) showed the twin-pore translocase mediates insertion. Reason: This is the primary biological process of TIM22. Extensively supported by experimental evidence from multiple groups (PMID:8955274, PMID:11864609, PMID:12637749, PMID:32591483). The IBA annotation is phylogenetically sound. Supporting Evidence: PMID:8955274 Tim22 is required for the import of proteins of the mitochondrial ADP/ATP carrier (AAC) family into the inner membrane PMID:11864609 The protein insertion complex of the mitochondrial inner membrane is crucial for import of the numerous multitopic membrane proteins with internal targeting signals |
| GO:0008320 protein transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for protein transmembrane transporter activity. GO:0008320 is defined as "Enables the transfer of a protein from one side of a membrane to the other." TIM22 does transfer proteins across/into the inner membrane. However, it is more precise to say TIM22 mediates insertion of polytopic membrane proteins INTO the membrane rather than transfer across it. The term is acceptable as the best available MF term for TIM22's core activity -- it forms a channel that enables protein translocation through the membrane. The IBA is phylogenetically sound. Reason: GO:0008320 is the best available MF term for the protein translocation channel activity of TIM22. Kovermann et al. (PMID:11864609) demonstrated that reconstituted TIM22 forms a "hydrophilic, high-conductance channel with distinct opening states and pore diameters" that mediates protein transfer. The IBA is phylogenetically correct. Supporting Evidence: PMID:11864609 Reconstituted Tim22 forms a hydrophilic, high-conductance channel with distinct opening states and pore diameters |
| GO:0071806 protein transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: IEA annotation inferred from GO:0008320 (protein transmembrane transporter activity) via logical inference. Since TIM22 enables protein transmembrane transporter activity, it follows that it is involved in protein transmembrane transport. This is a reasonable computational inference. Reason: Logically inferred from the IBA/IDA-supported GO:0008320 annotation. TIM22 mediates protein transmembrane transport (specifically insertion of carrier proteins into the inner membrane). The inference is sound, and this BP term is broader but not incorrect. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from UniProt subcellular location mapping. TIM22 is an integral multi-pass protein of the mitochondrial inner membrane. This is abundantly supported by experimental evidence (PMID:8955274, PMID:10397776, PMID:10648604, PMID:32591483). Reason: Correct localization. TIM22 is an integral inner membrane protein with multiple transmembrane helices. Redundant with experimental IDA annotations but not incorrect. |
| GO:0015031 protein transport | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword mapping (Protein transport, Translocation). GO:0015031 "protein transport" is a broad parent term. TIM22 is involved in protein transport, specifically insertion of carrier proteins into the inner membrane (GO:0045039). This IEA is not wrong but is very general. Reason: Correct but general. GO:0045039 (protein insertion into mitochondrial inner membrane) is the more specific and informative term, which is already annotated via IBA, IDA, and IMP. This IEA annotation to the parent term is redundant but acceptable. |
| GO:0042721 TIM22 mitochondrial import inner membrane insertion complex | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro mapping (IPR039175 TIM22). TIM22 is the core subunit of this complex. Redundant with IBA and IDA annotations for the same term. Reason: Correct. InterPro domain IPR039175 is specific to TIM22 family members. Redundant with experimental annotations but not incorrect. |
| GO:0045039 protein insertion into mitochondrial inner membrane | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro mapping (IPR039175 TIM22). Redundant with IBA, IDA, and IMP annotations for the same term. Reason: Correct. Redundant with experimental annotations but the InterPro mapping is sound. |
| GO:0005515 protein binding | IPI PMID:17099692 The Tim21 binding domain connects the preprotein translocase... | REMOVE | Summary: IPI annotation for protein binding based on interaction with Tim21 (P53220), from Albrecht et al. (PMID:17099692). That paper studied the Tim21 binding domain and its connections between TOM and TIM complexes. The interaction between TIM22 and TIM21 is documented in IntAct. However, GO:0005515 "protein binding" is uninformative -- it does not tell us what the interaction means functionally. Reason: GO:0005515 "protein binding" is a vague term that provides no functional information. Per curation guidelines, this term should be avoided. The interaction with Tim21 is better captured by the CC annotation to the TIM22 complex (GO:0042721). Furthermore, Albrecht et al. (PMID:17099692) focused on Tim21's role in connecting TOM and TIM23 complexes; the Tim22-Tim21 interaction is secondary and does not inform TIM22's core function. Supporting Evidence: PMID:17099692 Tim21, a subunit of the presequence translocase consisting of a membrane anchor and a carboxy-terminal domain exposed to the intermembrane space, directly connects the TOM and TIM23 complexes by binding to the intermembrane space domain of the Tom22 receptor |
| GO:0005743 mitochondrial inner membrane | IDA PMID:10648604 Tim18p, a new subunit of the TIM22 complex that mediates ins... | ACCEPT | Summary: IDA annotation for mitochondrial inner membrane localization from Koehler et al. (PMID:10648604). That study characterized the TIM22 complex and showed Tim22p is an integral membrane subunit of the inner membrane-localized 300-kDa complex. Reason: Experimentally demonstrated. TIM22 is an integral inner membrane protein, confirmed by co-migration with the 300-kDa TIM22 complex on nondenaturing gels (PMID:10648604) and by topology studies (UniProt). Supporting Evidence: PMID:10648604 a 300-kDa complex in the inner membrane, the TIM22 complex |
| GO:0045039 protein insertion into mitochondrial inner membrane | IDA PMID:10648604 Tim18p, a new subunit of the TIM22 complex that mediates ins... | ACCEPT | Summary: IDA annotation from Koehler et al. (PMID:10648604). This paper identified Tim18p as a new subunit of the TIM22 complex "that mediates insertion of imported proteins into the yeast mitochondrial inner membrane." Tim22p was established as the core channel subunit in this complex. Reason: Direct experimental evidence that the TIM22 complex containing Tim22p mediates protein insertion into the inner membrane (PMID:10648604). Supporting Evidence: PMID:10648604 Import of carrier proteins from the cytoplasm into the mitochondrial inner membrane of yeast is mediated by a distinct system consisting of two soluble 70-kDa protein complexes in the intermembrane space and a 300-kDa complex in the inner membrane, the TIM22 complex |
| GO:0005198 structural molecule activity | IDA PMID:32591483 Conserved regions of budding yeast Tim22 have a role in stru... | ACCEPT | Summary: IDA annotation for structural molecule activity from Kumar et al. (PMID:32591483). That study showed that conserved regions of Tim22 (IMS domain and TM4) are "critically required for interactions with the membrane-embedded subunits, including Tim54, Tim18, and Sdh3, and thereby maintain the functional architecture of the TIM22 translocase." Impairment of TIM22 complex assembly influenced translocase activity and cell viability. The structural role is real -- Tim22 is the scaffold around which the complex assembles. Reason: GO:0005198 "structural molecule activity" is defined as "The action of a molecule that contributes to the structural integrity of a complex." Kumar et al. (PMID:32591483) demonstrated that Tim22 regions are critical for maintaining the architecture and structural integrity of the TIM22 complex by mediating interactions with Tim54, Tim18, and Sdh3. This is a legitimate annotation -- Tim22 is both the channel and the structural core around which the complex assembles. Supporting Evidence: PMID:32591483 the intermembrane space (IMS) and transmembrane 4 (TM4) regions of Tim22 are critically required for interactions with the membrane-embedded subunits, including Tim54, Tim18, and Sdh3, and thereby maintain the functional architecture of the TIM22 translocase |
| GO:0005198 structural molecule activity | IMP PMID:32591483 Conserved regions of budding yeast Tim22 have a role in stru... | ACCEPT | Summary: IMP annotation for structural molecule activity from the same study (PMID:32591483). Mutations in conserved TIM22 regions disrupted complex assembly, demonstrating the structural role via mutant phenotype. Reason: Mutant analysis in Kumar et al. (PMID:32591483) showed that impairment of TIM22 regions disrupts complex assembly and stability, confirming the structural role by IMP evidence. Complements the IDA annotation above. Supporting Evidence: PMID:32591483 impairment of TIM22 complex assembly influences its translocase activity, the mitochondrial network, and the viability of cells lacking mitochondrial DNA |
| GO:0005743 mitochondrial inner membrane | IDA PMID:32591483 Conserved regions of budding yeast Tim22 have a role in stru... | ACCEPT | Summary: IDA annotation for inner membrane localization from Kumar et al. (PMID:32591483). That study confirmed Tim22 is active in the inner membrane, as expected for the core channel subunit. The GOA qualifier is "is_active_in." Reason: Tim22 is an integral multi-pass protein of the mitochondrial inner membrane, confirmed by multiple studies. This IDA is consistent with all other evidence. Supporting Evidence: PMID:32591483 the TIM22 complex enables the integration of complex membrane proteins with internal targeting signals into the inner membrane |
| GO:0045039 protein insertion into mitochondrial inner membrane | IDA PMID:32591483 Conserved regions of budding yeast Tim22 have a role in stru... | ACCEPT | Summary: IDA annotation for protein insertion from Kumar et al. (PMID:32591483). Direct assays showed Tim22 is critically required for the translocase activity of the TIM22 complex. Reason: Direct experimental evidence from Kumar et al. (PMID:32591483). Tim22 is the core channel; its conserved regions are required for translocase activity. Supporting Evidence: PMID:32591483 the TIM22 complex enables the integration of complex membrane proteins with internal targeting signals into the inner membrane |
| GO:0045039 protein insertion into mitochondrial inner membrane | IMP PMID:32591483 Conserved regions of budding yeast Tim22 have a role in stru... | ACCEPT | Summary: IMP annotation for protein insertion from Kumar et al. (PMID:32591483). Mutant analysis of conserved Tim22 regions showed impaired translocase activity. Reason: Mutant phenotype evidence from Kumar et al. (PMID:32591483). Disruption of conserved Tim22 regions impaired protein insertion activity of the TIM22 complex. Supporting Evidence: PMID:32591483 impairment of TIM22 complex assembly influences its translocase activity |
| GO:0005739 mitochondrion | HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph... | ACCEPT | Summary: HDA annotation for mitochondrion localization from Renvoise et al. (PMID:24769239), a quantitative mitochondrial proteomics study. TIM22 was identified as a mitochondrial protein by high-throughput mass spectrometry. Reason: Correct. TIM22 is a mitochondrial protein. The HDA evidence from proteomics (PMID:24769239) is a broader CC term than the more specific "mitochondrial inner membrane" (GO:0005743) but is not incorrect. |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | ACCEPT | Summary: HDA annotation for mitochondrion localization from Reinders et al. (PMID:16823961), a comprehensive yeast mitochondrial proteome analysis using multidimensional separation techniques. Reason: Correct. TIM22 was identified in the yeast mitochondrial proteome (PMID:16823961). Redundant with other CC annotations but acceptable. |
| GO:0008320 protein transmembrane transporter activity | IDA PMID:11864609 Tim22, the essential core of the mitochondrial protein inser... | ACCEPT | Summary: IDA annotation for protein transmembrane transporter activity from Kovermann et al. (PMID:11864609). This landmark paper demonstrated that reconstituted Tim22 forms a "hydrophilic, high-conductance channel with distinct opening states and pore diameters" that is "voltage-activated and specifically responds to an internal targeting signal." The paper showed Tim22 is "the only essential membrane-integrated subunit of the complex" and that "a protein insertion complex can combine three essential functions, signal recognition, channel formation, and energy transduction, in one central component." Reason: Strong experimental evidence. Kovermann et al. (PMID:11864609) performed reconstitution and electrophysiology experiments demonstrating that Tim22 alone forms a functional protein-translocating channel. This is the definitive evidence for TIM22's MF. Supporting Evidence: PMID:11864609 Reconstituted Tim22 forms a hydrophilic, high-conductance channel with distinct opening states and pore diameters. The channel is voltage-activated and specifically responds to an internal targeting signal, but not to presequences PMID:11864609 a protein insertion complex can combine three essential functions, signal recognition, channel formation, and energy transduction, in one central component |
| GO:0030943 mitochondrion targeting sequence binding | IDA PMID:11864609 Tim22, the essential core of the mitochondrial protein inser... | MODIFY | Summary: IDA annotation for mitochondrion targeting sequence binding from Kovermann et al. (PMID:11864609). The study showed that the Tim22 channel "specifically responds to an internal targeting signal, but not to presequences." This demonstrates signal-gated channel activity where TIM22 recognizes internal targeting signals of carrier proteins. Reason: GO:0030943 (mitochondrion targeting sequence binding) is obsolete in the current GO release (consider GO:0140436 / GO:0008320). Tim22 is the internal-signal-gated carrier translocase channel rather than a targeting-signal receptor; its signal response is part of its protein-conducting channel activity, captured by GO:0008320 rather than the receptor MF GO:0140436. TIM22 already carries GO:0008320 (IBA and IDA), so this MODIFY folds the row into that existing annotation and asserts nothing new. Experimental evidence from electrophysiology showing signal-gated response to internal targeting signals (PMID:11864609). TIM22 specifically responds to internal signals, not N-terminal presequences. Proposed replacements: transmembrane protein transporter activity Supporting Evidence: PMID:11864609 The channel is voltage-activated and specifically responds to an internal targeting signal, but not to presequences |
| GO:0042721 TIM22 mitochondrial import inner membrane insertion complex | IDA PMID:10637294 Tim18p is a new component of the Tim54p-Tim22p translocon in... | ACCEPT | Summary: IDA annotation from Kerscher et al. (PMID:10637294). This study identified TIM18 as a new component of the Tim54p-Tim22p translocon and demonstrated that Tim22p is part of the approximately 300-kDa complex by blue native electrophoresis and co-immunoprecipitation. Reason: Direct biochemical evidence (co-IP, BN-PAGE) demonstrating Tim22p as a core component of the TIM22 complex (PMID:10637294). Supporting Evidence: PMID:10637294 Tim54p and Tim22p can be coimmune precipitated with the Tim18 protein; and Tim18p, along with Tim54p and Tim22p, is detected in an approximately 300-kDa complex after blue native electrophoresis |
| GO:0042721 TIM22 mitochondrial import inner membrane insertion complex | IDA PMID:10648604 Tim18p, a new subunit of the TIM22 complex that mediates ins... | ACCEPT | Summary: IDA annotation from Koehler et al. (PMID:10648604). The study characterized the TIM22 complex composition, confirming Tim22p as a core integral membrane subunit alongside Tim54p, with peripheral subunits Tim9p, Tim10p, and Tim12p. Reason: Biochemical characterization of the TIM22 complex demonstrating Tim22p as a core subunit (PMID:10648604). Supporting Evidence: PMID:10648604 The TIM22 complex contains the peripheral subunits Tim9p, Tim10p, and Tim12p and the integral membrane subunits Tim22p and Tim54p |
| GO:0045039 protein insertion into mitochondrial inner membrane | IMP PMID:10648604 Tim18p, a new subunit of the TIM22 complex that mediates ins... | ACCEPT | Summary: IMP annotation from Koehler et al. (PMID:10648604). Deletion of Tim18p (a complex partner) impaired import of precursor proteins, demonstrating the role of the TIM22 complex in protein insertion by mutant phenotype. Reason: Mutant phenotype evidence supporting the role of the TIM22 complex in protein insertion (PMID:10648604). Although the mutation was in Tim18p rather than Tim22p directly, it demonstrates the functional requirement of the complex. Supporting Evidence: PMID:10648604 It also impairs the import of several precursor proteins into isolated mitochondria, and lowers the apparent mass of the TIM22 complex |
| GO:0045039 protein insertion into mitochondrial inner membrane | IMP PMID:8955274 Import of carrier proteins into the mitochondrial inner memb... | ACCEPT | Summary: IMP annotation from the founding paper by Sirrenberg et al. (PMID:8955274). This study first identified Tim22 as required for import of ADP/ATP carrier family members into the inner membrane, and showed that Tim22 is in an assembly distinct from the Tim23-Tim17 complex. Reason: Foundational experimental evidence. Sirrenberg et al. (PMID:8955274) first demonstrated that "Tim22 is required for the import of proteins of the mitochondrial ADP/ATP carrier (AAC) family into the inner membrane" and that "Import of proteins of the AAC family is independent of Tim23." Supporting Evidence: PMID:8955274 Tim22 is required for the import of proteins of the mitochondrial ADP/ATP carrier (AAC) family into the inner membrane. Members of the yeast AAC family are synthesized without matrix targeting signals PMID:8955274 Import of proteins of the AAC family is independent of Tim23, and import of matrix targeting signals containing preproteins is independent of Tim22 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-SCE-1252258 | ACCEPT | Summary: TAS annotation from Reactome pathway R-SCE-1252258 "TIM22 complex inserts proteins into inner membrane." TIM22 is indeed located in the inner membrane. Reason: Correct localization. Reactome pathway annotation is consistent with all experimental evidence. |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-SCE-1252255 | MARK AS OVER ANNOTATED | Summary: TAS annotation from Reactome pathway R-SCE-1252255 "TOM40:TOM70 complex translocates proteins from the cytosol to the mitochondrial intermembrane space." This Reactome pathway describes the TOM-mediated import step, not TIM22 function per se. TIM22 does have domains exposed to the IMS (the N-terminal and C-terminal regions per UniProt topology), so there is some basis for IMS localization, but the primary localization is the inner membrane itself. This appears to be a Reactome annotation associating TIM22 with a pathway step where it is a participant rather than indicating its primary localization. Reason: TIM22 is an integral inner membrane protein, not an IMS protein. While it has IMS-exposed domains (N-terminal and C-terminal regions per UniProt topology), its primary localization is the inner membrane (GO:0005743), which is already well-annotated. The Reactome pathway R-SCE-1252255 describes TOM-mediated translocation to the IMS, not TIM22's localization. Annotating TIM22 to the IMS is misleading. |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-SCE-1252258 | MARK AS OVER ANNOTATED | Summary: TAS annotation from Reactome pathway R-SCE-1252258 "TIM22 complex inserts proteins into inner membrane." Same concern as the other IMS annotation -- TIM22 is an integral inner membrane protein with IMS-exposed domains, but its primary CC is the inner membrane. Reason: TIM22 is an integral inner membrane protein. While the TIM22 complex operates at the interface between the IMS and the inner membrane, and Tim22 has IMS-exposed domains, annotating it to GO:0005758 (mitochondrial intermembrane space) suggests it is a soluble IMS protein, which is incorrect. The inner membrane annotation (GO:0005743) is the correct and sufficient CC term. |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-SCE-1252259 | MARK AS OVER ANNOTATED | Summary: TAS annotation from Reactome pathway R-SCE-1252259 "TIM9:TIM10 binds hydrophobic proteins." This pathway describes the action of the small TIM chaperones (Tim9-Tim10) in the IMS, not TIM22 itself. TIM22 is listed as a participant in the broader mitochondrial import pathway but its primary localization is the inner membrane. Reason: Same rationale as other IMS annotations. TIM22 is an inner membrane protein, not an IMS protein. This Reactome pathway (R-SCE-1252259) describes TIM9:TIM10 function in the IMS, and TIM22 is merely a downstream partner. |
| GO:0005829 cytosol | TAS Reactome:R-SCE-1252255 | REMOVE | Summary: TAS annotation from Reactome pathway R-SCE-1252255. This likely reflects that TIM22 precursor protein passes through the cytosol during its own import. However, mature TIM22 is an integral inner membrane protein and is not a cytosolic protein. Reason: TIM22 is not a cytosolic protein. It is an integral multi-pass protein of the mitochondrial inner membrane. While the TIM22 precursor transiently exists in the cytosol during its own biogenesis (like all nuclear-encoded mitochondrial proteins), the mature protein resides exclusively in the inner membrane. The Reactome pathway R-SCE-1252255 describes TOM-mediated import from the cytosol, but this does not make TIM22 a cytosolic protein. |
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