TOMM20

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005742 mitochondrial outer membrane translocase complex	IBA GO_REF:0000033	ACCEPT	Summary: TOMM20 is a well-established subunit of the TOM complex. Phylogenetic inference (IBA) for GO:0005742 is fully consistent with extensive experimental evidence showing TOMM20 as a core receptor component of the TOM complex in humans (PMID:18331822, PMID:35733257, PMID:40080546). The cryo-EM structure of the human TOM complex at 2.53 A resolution directly shows TOMM20 as a stoichiometric component (PMID:35733257). UniProt confirms membership in the TOM complex comprising TOMM5, TOMM6, TOMM7, TOMM20, TOMM22, and TOMM40. Reason: Core component of TOMM20 function. IBA annotation is well supported by multiple independent structural and biochemical studies in human cells. Supporting Evidence: PMID:35733257 As a consequence, we resolved the human TOM complex containing Tom22 and Tom20 cytosolic domains at 3.74 Å PMID:18331822 We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7.
GO:0030943 mitochondrion targeting sequence binding	IBA GO_REF:0000033	MODIFY	Summary: TOMM20 is the primary receptor for N-terminal mitochondrial targeting sequences (presequences). This IBA annotation is strongly supported by direct experimental evidence including the structural determination of the Tom20 cytosolic domain binding groove that recognizes amphipathic helical presequences (PMID:35733257), pull-down assays showing Tom20 binds Su9-DHFR-EGFP presequence fusion protein (PMID:35733257), and earlier work showing specific binding to mitochondrial preproteins but not proteins destined for other organelles (PMID:14557246). This is the core molecular function of TOMM20. Reason: GO:0030943 (mitochondrion targeting sequence binding) is obsolete in the current GO release (consider GO:0140436 / GO:0008320). TOMM20 is a cytosolic-side presequence receptor, so the receptor MF GO:0140436 is the designated replacement. This is the primary molecular function of TOMM20 -- recognizing mitochondrial targeting sequences. Extensively validated by structural and biochemical evidence. Proposed replacements: mitochondrial signal sequence receptor activity Supporting Evidence: PMID:35733257 both Tom20 and Tom22 were pulled down by the DHFR-EGFP protein fused with the presequence of subunit 9 of F0-ATPase (Su9) (42), but not by DHFR-EGFP protein without Su9, suggesting that Tom22 indeed forms a complex with the presequence as Tom20. PMID:14557246 Preproteins with NH2-terminal presequences are initially recognized by the receptor Tom20, although preproteins with internal targeting signals such as carrier proteins are recognized preferentially by Tom70.
GO:0008320 protein transmembrane transporter activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation of TOMM20 to GO:0008320 "protein transmembrane transporter activity" is somewhat imprecise. TOMM20 itself is a receptor that recognizes presequences and hands substrates off to the TOMM40 pore. It does not form the translocation channel. TOMM40 is the actual pore-forming subunit. However, the TOM complex as a whole does function as a protein transmembrane transporter, and TOMM20 is an essential component of that activity. The IBA annotation likely reflects the holistic function of the complex. This is acceptable at the broader level since TOMM20 contributes to the overall transporter activity, though it is the receptor subunit rather than the channel. Reason: While TOMM20 is specifically the receptor subunit rather than the pore, it is an integral and essential part of the protein translocation machinery. The IBA annotation reflects the conserved role of TOM20 family members in the protein import pathway. This broad annotation is phylogenetically well supported. Supporting Evidence: PMID:35733257 Tom20, as the major import receptor, together with Tom70 and Tom22 target mitochondrial precursor proteins in the cytosol precisely
GO:0016031 tRNA import into mitochondrion	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation of TOMM20 to GO:0016031 "tRNA import into mitochondrion" is unexpected. While there is evidence in some organisms (yeast, plants) that the TOM complex may participate in tRNA import into mitochondria, this is not a well-established function of human TOMM20. The primary literature on human TOMM20 focuses exclusively on protein import. The IBA inference may reflect functions established in other organisms in the Tom20 family phylogeny. This is not a core function of TOMM20 in humans and should be flagged. Reason: The IBA phylogenetic inference may be valid for some family members but this is not a well-documented function in human cells. TOMM20 is primarily characterized as a protein import receptor. Keeping as non-core since the IBA inference has phylogenetic basis but it does not represent the primary function of human TOMM20.
GO:0030150 protein import into mitochondrial matrix	IBA GO_REF:0000033	ACCEPT	Summary: TOMM20 recognizes presequence-bearing preproteins destined for the mitochondrial matrix and inner membrane. The TOM complex, of which TOMM20 is the primary presequence receptor, is the essential entry gate for matrix-targeted proteins. This IBA annotation is well supported by the known biology: TOMM20 preferentially handles precursors destined for the matrix and inner membrane (deep research, Su et al. 2024). Knockdown of small Tom proteins compromises matrix import of preprotein (PMID:18331822). Reason: Core biological process for TOMM20. As the presequence receptor of the TOM complex, TOMM20 is essential for protein import into the mitochondrial matrix. Supporting Evidence: PMID:18331822 Matrix import of preprotein was affected by double knockdown of any combination of small Tom proteins. PMID:35733257 the precursor proteins can be recognized and transferred from the cytosol to four different locations of mitochondria: the outer membrane (OM), the inner membrane (IM), the intermembrane space (IMS), and the matrix
GO:0005741 mitochondrial outer membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location mapping. TOMM20 is anchored in the mitochondrial outer membrane via an N-terminal transmembrane helix (residues 7-24, per UniProt). This is extensively confirmed by multiple IDA experiments and structural studies (PMID:25997101, PMID:40080546, PMID:35733257). Reason: Correct localization. TOMM20 is an integral membrane protein of the mitochondrial outer membrane. The IEA mapping is fully consistent with experimental evidence.
GO:0005742 mitochondrial outer membrane translocase complex	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro domain mapping. TOMM20 contains the MAS20 domain (PF02064/IPR002056) which is diagnostic for the Tom20 family of mitochondrial import receptors. This correctly maps to TOM complex membership. Consistent with the IBA annotation and extensive experimental evidence. Reason: Correct. The InterPro-based inference is fully supported by experimental data showing TOMM20 is a component of the TOM complex.
GO:0006605 protein targeting	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro mapping. GO:0006605 "protein targeting" is a broad parent term. TOMM20 participates in protein targeting to the mitochondrion specifically. While correct, this is less informative than the more specific GO:0006626 "protein targeting to mitochondrion" which is also annotated to TOMM20 (IDA from PMID:14557246). The broader IEA annotation is acceptable as it does not conflict with the more specific terms. Reason: Correct but broad. The IEA mapping captures the general protein targeting role of TOMM20. More specific terms (GO:0006626, GO:0030150) are also present in the annotation set.
GO:0006886 intracellular protein transport	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro mapping. GO:0006886 "intracellular protein transport" is a broad parent term that is technically correct for TOMM20 as it mediates transport of nuclear-encoded proteins into the mitochondrion. More specific process terms are present in the annotation set. Reason: Correct but broad. The IEA mapping is consistent with TOMM20 function in mitochondrial protein import. Not misleading even though more specific terms exist.
GO:0015031 protein transport	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping ("Protein transport"). This is a very broad term. TOMM20 is part of the protein import machinery of mitochondria, so this is technically correct but uninformative. More specific annotations already exist in the set. Reason: Correct but very broad parent term. Acceptable as an IEA that is consistent with the more specific experimental annotations.
GO:0030150 protein import into mitochondrial matrix	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro mapping. Duplicate of the IBA annotation to the same term. Both are correct -- TOMM20 is essential for protein import into the mitochondrial matrix as the primary presequence receptor of the TOM complex. Reason: Correct. Consistent with the IBA annotation and extensive experimental evidence for TOMM20 role in matrix protein import.
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	REMOVE	Summary: IPI annotation from a large-scale crosslinking mass spectrometry study of histone interactions in cell nuclei (PMID:30021884). TOMM20 appearing in this dataset is likely a contaminant or non-specific interaction, as TOMM20 is a mitochondrial outer membrane protein with no known nuclear function. The term "protein binding" is uninformative and does not reflect the actual molecular function of TOMM20. Reason: The annotation to "protein binding" from a nuclear crosslinking MS study is uninformative and likely reflects a non-specific or contaminating interaction. TOMM20 is a mitochondrial protein with no known nuclear role. "Protein binding" does not capture any meaningful functional information about TOMM20.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	REMOVE	Summary: IPI annotation from the OpenCell project (PMID:35271311), a large-scale endogenous tagging study. While TOMM20 certainly binds proteins (it is a receptor for preproteins and part of the TOM complex), the generic term "protein binding" does not convey any functional information. TOMM20 has more specific molecular function annotations (GO:0140436 mitochondrial signal sequence receptor activity, the replacement for the obsolete GO:0030943) that better capture its binding activity. Reason: "Protein binding" is uninformative for TOMM20. The specific binding function is already captured by GO:0140436 "mitochondrial signal sequence receptor activity" (replacement for the obsolete GO:0030943). Per curation guidelines, generic protein binding annotations should be avoided in favor of more informative terms.
GO:0005739 mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation from Ensembl Compara ortholog transfer. TOMM20 is a mitochondrial protein, confirmed by multiple IDA annotations and structural studies. The broader "mitochondrion" term is less specific than "mitochondrial outer membrane" but is not incorrect. Reason: Correct. TOMM20 is a mitochondrial protein. More specific localization terms (mitochondrial outer membrane, TOM complex) are also present.
GO:0005740 mitochondrial envelope	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from combined automated methods. GO:0005740 "mitochondrial envelope" is correct but less specific than "mitochondrial outer membrane" (GO:0005741). TOMM20 is specifically in the outer membrane, not the inner membrane or intermembrane space. The annotation is not wrong, just broad. Reason: Correct but broad. TOMM20 is in the mitochondrial outer membrane, which is part of the mitochondrial envelope. More specific annotations exist.
GO:0071944 cell periphery	IEA GO_REF:0000107	REMOVE	Summary: IEA annotation from Ensembl Compara ortholog transfer. GO:0071944 "cell periphery" is unexpected for TOMM20, which is a mitochondrial outer membrane protein. There is no strong evidence that TOMM20 localizes to the cell periphery. This may result from erroneous ortholog transfer or a broad interpretation from a high-throughput study. TOMM20 is not primarily a cell periphery protein. Reason: TOMM20 is a mitochondrial outer membrane protein with no established localization to the cell periphery. This IEA annotation is likely erroneous or reflects non-specific detection in a high-throughput experiment. The primary localization is well established as the mitochondrial outer membrane.
GO:0097225 sperm midpiece	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara ortholog transfer. The sperm midpiece is rich in mitochondria (the mitochondrial sheath), so detection of TOMM20 there is expected for any mitochondrial outer membrane protein. This annotation is technically correct but reflects the general mitochondrial localization rather than a sperm-specific function. Reason: Correct in the sense that mitochondria are abundant in the sperm midpiece and TOMM20 would be present there. However, this reflects general mitochondrial localization rather than a specific role in sperm biology. Not a core annotation for understanding TOMM20 function.
GO:0140494 migrasome	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation from Ensembl Compara ortholog transfer. Migrasomes are cellular organelles released during cell migration. TOMM20 appearing in migrasomes could reflect mitochondrial content within migrasomes, which has been observed. However, this is not a primary localization of TOMM20 and likely reflects incidental detection of mitochondrial proteins in migrasomes. Reason: TOMM20 may be present in migrasomes due to mitochondrial content, but this does not represent a specific function or primary localization of TOMM20. Keeping as non-core since migrasomes can contain mitochondria.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on immunofluorescence data curation. TOMM20 is routinely used as a mitochondrial marker in immunofluorescence studies, making this one of the most well-supported localization annotations possible. TOMM20 antibody staining is a standard method for visualizing mitochondria. Reason: Well established. TOMM20 is one of the most commonly used mitochondrial markers in immunofluorescence.
GO:0005741 mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: NAS annotation citing Kato & Mihara 2008, which identified Tom5 and Tom6 in the human TOM complex. The paper immuno-isolated the TOM complex from HeLa cells and confirmed TOMM20 as a component, along with other subunits. As a TOM complex subunit, TOMM20 is in the mitochondrial outer membrane. Reason: Correct. PMID:18331822 confirms TOMM20 as part of the TOM complex in human cells, which is in the mitochondrial outer membrane. Supporting Evidence: PMID:18331822 We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7.
GO:0045040 protein insertion into mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	MARK AS OVER ANNOTATED	Summary: NAS annotation to GO:0045040 "protein insertion into mitochondrial outer membrane" from PMID:18331822. This GO term describes the process of inserting proteins from outside the organelle into the mitochondrial outer membrane, mediated by large outer membrane translocase complexes. While the TOM complex does handle some outer membrane proteins, this process is more specifically associated with the SAM complex (GO:0001401) and MIM complex (GO:0140595). TOMM20 primarily recognizes presequence-bearing proteins destined for the matrix and inner membrane, not outer membrane insertion. The TOM complex mediates initial recognition and translocation across the outer membrane, but insertion into the outer membrane is primarily a SAM/MIM function. Reason: TOMM20 is the presequence receptor primarily handling matrix/inner membrane destined precursors. Protein insertion into the mitochondrial outer membrane is primarily mediated by the SAM complex, not the TOM complex receptor subunit TOMM20. While TOM participates in the initial recognition step for beta-barrel precursors, TOMM20 specifically recognizes N-terminal presequences, not the signals used by outer membrane beta-barrel proteins.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: HTP annotation from a quantitative high-confidence human mitochondrial proteome study (PMID:34800366). TOMM20 was identified as a mitochondrial protein with high confidence, consistent with its well-established localization. Reason: Correct. High-throughput proteomics confirms TOMM20 in the mitochondrial proteome, consistent with all other evidence.
GO:0005515 protein binding	IPI PMID:38848361 Mechanism of human PINK1 activation at the TOM complex in a ...	REMOVE	Summary: IPI annotation from PMID:38848361 (Raimi et al. 2024), which demonstrated that TOMM20 interacts with PINK1 in a reconstituted system. The study showed that TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and mapped sites of interaction using AlphaFold modeling and mutagenesis. While the interaction with PINK1 is genuine and functionally significant, "protein binding" does not capture the specific nature of this interaction. A more informative term would describe the PINK1-TOMM20 interaction in the context of mitophagy signaling. Reason: The PINK1-TOMM20 interaction is real and important, but "protein binding" is uninformative per curation guidelines. The specific biological context is PINK1 activation at damaged mitochondria, which is better captured by process annotations. TOMM20 binding to PINK1 is part of its function as a TOM complex receptor, already captured by GO:0140436 (replacement for the obsolete GO:0030943) and GO:0005742. Supporting Evidence: PMID:38848361 We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modeling and mutagenesis.
GO:0030943 mitochondrion targeting sequence binding	IDA PMID:35733257 Structural basis of Tom20 and Tom22 cytosolic domains as the...	MODIFY	Summary: IDA annotation from Su et al. 2022 (PMID:35733257), which determined the cryo-EM structure of the human TOM complex at 2.53 A and captured the TOM complex with Tom20 and Tom22 cytosolic domains at 3.74 A. Pull-down experiments directly demonstrated that Tom20 binds the presequence of Su9-DHFR-EGFP but not DHFR-EGFP without the presequence, confirming specific mitochondrial targeting sequence binding. This is the core molecular function of TOMM20. Reason: GO:0030943 (mitochondrion targeting sequence binding) is obsolete in the current GO release (consider GO:0140436 / GO:0008320). TOMM20 is a cytosolic-side presequence receptor, so the receptor MF GO:0140436 is the designated replacement. Direct experimental evidence demonstrating TOMM20 binds mitochondrial targeting sequences specifically. This is the best-supported core molecular function annotation for TOMM20. Proposed replacements: mitochondrial signal sequence receptor activity Supporting Evidence: PMID:35733257 both Tom20 and Tom22 were pulled down by the DHFR-EGFP protein fused with the presequence of subunit 9 of F0-ATPase (Su9) (42), but not by DHFR-EGFP protein without Su9, suggesting that Tom22 indeed forms a complex with the presequence as Tom20.As the cytosolic domain of Tom20 is the main site for presequence binding
GO:0005739 mitochondrion	IDA PMID:32848200 Ttm50 facilitates calpain activation by anchoring it to calc...	ACCEPT	Summary: IDA annotation from PMID:32848200. The title of this paper is about Ttm50 facilitating calpain activation. TOMM20 was likely used as a mitochondrial marker in this study. The localization to mitochondrion is well established. Reason: Correct localization. TOMM20 is a mitochondrial protein. Likely used as a marker in this study confirming mitochondrial localization.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5205649	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-5205649 "p62 links damaged mitochondria to LC3." TOMM20 is placed at the mitochondrial outer membrane in this mitophagy pathway, which is correct. TOMM20 is a ubiquitination substrate of PRKN during mitophagy. Reason: Correct localization within the context of the PINK1-PRKN mitophagy pathway. TOMM20 is a substrate of PRKN ubiquitination on the mitochondrial outer membrane.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5205663	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-5205663 "LC3 binds the autophagosome membrane Atg5-Atg12 complex." TOMM20 localization to mitochondrial outer membrane in this autophagy context is correct. Reason: Correct localization. Duplicate evidence for TOMM20 at the mitochondrial outer membrane from the mitophagy pathway context.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5205673	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-5205673 "p62 binds ubiquitinated mitochondrial substrates." TOMM20 is a known ubiquitination substrate on the mitochondrial outer membrane during mitophagy. Correct localization. Reason: Correct. TOMM20 is ubiquitinated by PRKN at K35, K56, K61, and K68 on the mitochondrial outer membrane during mitophagy.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9824888	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9824888 "OPTN, TBK1 bind ubiquitinated MOM proteins." TOMM20 is a ubiquitinated MOM substrate. Correct localization. Reason: Correct localization in the mitophagy pathway context.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9824892	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9824892 "MAP1LC3B binds p-S-OPTN bound to Ub-mitochondria." TOMM20 at mitochondrial outer membrane in mitophagy context. Correct localization. Reason: Correct localization. Redundant with other mitochondrial outer membrane TAS annotations from Reactome mitophagy pathway.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9824894	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9824894 "TBK1 is phosphorylated within TBK1:OPTN:Ub-mitochondrial proteins." TOMM20 at mitochondrial outer membrane. Correct localization. Reason: Correct localization in the mitophagy signaling context.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9824897	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9824897 "p-S-TBK1 phosphorylates OPTN." TOMM20 at mitochondrial outer membrane in the mitophagy signaling cascade. Correct localization. Reason: Correct localization.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9834070	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9834070 "PRKN ubiquitinates MOM substrates." TOMM20 is a direct ubiquitination substrate of PRKN on the mitochondrial outer membrane (PMID:24896179, PMID:25621951 per UniProt). Correct and specifically relevant. Reason: Correct. TOMM20 is directly ubiquitinated by PRKN at K35, K56, K61, and K68 on the mitochondrial outer membrane.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9840807	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9840807 "OPTN binds ATG9A." TOMM20 at mitochondrial outer membrane in the mitophagy context. Correct localization. Reason: Correct localization.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9834945	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9834945 "PINK1 phosphorylates Ub on MOM proteins." The Reactome entry explicitly lists TOMM20 as one of the MOM proteins whose ubiquitin moieties are phosphorylated by PINK1. Correct localization. Reason: Correct. TOMM20 is specifically named as a PINK1 substrate in this Reactome pathway.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9835009	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9835009 "PRKN binds p-S-Ub:MOM proteins." TOMM20 at mitochondrial outer membrane as a ubiquitinated substrate for PRKN binding. Correct localization. Reason: Correct localization in the PINK1-PRKN mitophagy pathway.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9835011	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9835011 "PINK1 phosphorylates PRKN at S65." TOMM20 at mitochondrial outer membrane in the context of PINK1 activation at the TOM complex. Correct localization. Reason: Correct localization.
GO:0097225 sperm midpiece	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation from manual transfer by curator judgment. The sperm midpiece contains the mitochondrial sheath, which is densely packed with mitochondria. TOMM20, as a ubiquitous mitochondrial outer membrane protein, would be present in sperm midpiece mitochondria. This is a valid localization but not specific to TOMM20 function. Reason: Correct due to mitochondrial content of the sperm midpiece. Not a core annotation for understanding TOMM20 function; it simply reflects the general mitochondrial localization in a specialized cell type.
GO:0005739 mitochondrion	IDA PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	ACCEPT	Summary: IDA annotation from PMID:20628368 (Liu et al. 2010), a study on Tom70 mediating activation of IRF3 on mitochondria. TOMM20 was used as a mitochondrial marker or co-localization control in this study. UniProt cites this paper for subcellular location evidence. Correct localization. Reason: Correct. TOMM20 mitochondrial localization confirmed in a study where it was used as a mitochondrial marker.
GO:0005739 mitochondrion	IDA PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	ACCEPT	Summary: IDA annotation from PMID:25327288 (Dowdle et al. 2014), a study on VPS34 inhibitor and autophagy/ferritinophagy. TOMM20 was likely used as a mitochondrial marker in this study. Correct localization. Reason: Correct localization. TOMM20 is widely used as a mitochondrial marker.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5696872	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-5696872 "USP30 deubiquitinates Ub-MOM proteins." TOMM20 is a substrate of both PRKN (ubiquitination) and USP30 (deubiquitination) at the mitochondrial outer membrane (PMID:24896179). Correct and functionally relevant localization. Reason: Correct. TOMM20 is a known substrate of USP30 deubiquitination on the mitochondrial outer membrane, documented in PMID:24896179.
GO:0005741 mitochondrial outer membrane	IDA PMID:25997101 QIL1 is a novel mitochondrial protein required for MICOS com...	ACCEPT	Summary: IDA annotation from PMID:25997101 (Guarani et al. 2015), a study on QIL1/MICOS complex. TOMM20 was used as a mitochondrial outer membrane marker via immunofluorescence co-staining with MICOS subunits. The paper states alpha-TOMM20 was used for immunofluorescence analysis to verify mitochondrial localization. UniProt also cites this paper for subcellular location evidence. Correct localization. TOMM20's outer membrane topology is independently corroborated by proteinase K protection assays in PMID:40263465, which use TOM20 as the canonical outer membrane (OM) marker. That structural study (cryo-EM; PDB 9J79, 9J7A, 9J7B, 9JCE) further shows that the TOM20 cytosolic tail (residues 25-145, four-helix bundle alpha3-alpha6) directly binds the N-terminal ANK1 repeat of FEM1B, recruiting the CRL2-FEM1B E3 ubiquitin ligase to the outer mitochondrial membrane to control PLD6 degradation and mitochondrial dynamics -- a specialized scaffolding role distinct from the canonical presequence import-receptor function. Reason: Correct. TOMM20 used as a mitochondrial outer membrane marker in immunofluorescence studies, confirming its localization. Supporting Evidence: PMID:25997101 Confocal microscopy after immunostaining with α-HA and α-TOMM20 verified that each protein was targeted to mitochondria in HeLa cells PMID:40263465 both endogenous (Extended Data Fig. 5d) and exogenous (Fig. 4d) FEM1B proteins are sensitive to proteolysis, similar to the outer membrane (OM) marker TOM20 PMID:40263465 GST pulldown assays demonstrated a direct association between FEM1B and the cytoplasmic tail of TOM20 (Fig. 4f). Notably, significantly more FEM1B was precipitated using the GST-TOM20 tail (Fig. 4f) compared to the PLD6 tail (Fig. 1j), indicating a stronger affinity for TOM20. PMID:40263465 the four-helix bundle of TOM20 (α3-α6) spanning residues 68–125 was unambiguously fitted into the map, and primarily interacts with ANK1 region located in the N-terminus of FEM1B [...] These findings collectively support the conclusion that TOM20 interacts with FEM1B to mediate its mitochondrial targeting and facilitate the formation of an active CRL2FEM1B E3 complex at the outer mitochondrial membrane.
GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site	IDA PMID:23455425 Autophagosomes form at ER-mitochondria contact sites.	KEEP AS NON CORE	Summary: IDA annotation from PMID:23455425 (Hamasaki et al. 2013), "Autophagosomes form at ER-mitochondria contact sites." TOMM20 was likely detected at MAM (mitochondria-associated ER membrane) contact sites. As an outer membrane protein of mitochondria, TOMM20 would be present at ER-mitochondria contact regions where the outer membrane faces the ER. This is consistent with its localization but may not represent a specific function at MAMs. Reason: TOMM20 as a mitochondrial outer membrane protein could be present at MAM contact sites, but there is no evidence that TOMM20 has a specific functional role at these sites. This likely reflects detection of the mitochondrial outer membrane at ER contact points rather than a specific MAM-targeted function.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5205661	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-5205661 "Pink1 is recruited from the cytoplasm to the mitochondria." TOMM20 at the mitochondrial outer membrane in the context of PINK1 import. Recent evidence shows TOMM20 directly gates PINK1 activity and mediates tethering of TOM and TIM23 translocases upon mitochondrial stress (PMID:38416681 cited in UniProt). Correct and functionally relevant. Reason: Correct. TOMM20 is at the mitochondrial outer membrane where it participates in PINK1 stabilization upon mitochondrial depolarization.
GO:0005515 protein binding	IPI PMID:20231292 Identification and characterization of mitochondrial targeti...	REMOVE	Summary: IPI annotation from PMID:20231292 (Li et al. 2010), which identified the mitochondrial targeting sequence of APEX1 (apurinic/apyrimidinic endonuclease 1) and showed it interacts with TOMM20 for mitochondrial import. UniProt confirms this interaction. However, "protein binding" is uninformative. The actual function demonstrated is that TOMM20 recognizes the MTS of APEX1, which is already captured by GO:0140436 "mitochondrial signal sequence receptor activity" (replacement for the obsolete GO:0030943). Reason: The interaction between TOMM20 and APEX1 is genuine and reflects TOMM20 recognizing the mitochondrial targeting sequence of APEX1. However, "protein binding" is uninformative. This function is already captured by GO:0140436 "mitochondrial signal sequence receptor activity" (replacement for the obsolete GO:0030943). Per curation guidelines, avoid generic protein binding annotations. Supporting Evidence: PMID:20231292 Identification and characterization of mitochondrial targeting sequence of human apurinic/apyrimidinic endonuclease 1.
GO:0005742 mitochondrial outer membrane translocase complex	TAS PMID:15644312 Dissection of the mitochondrial import and assembly pathway ...	ACCEPT	Summary: TAS annotation from PMID:15644312 (Humphries et al. 2005), which dissected the import and assembly pathway for human Tom40. The study confirms TOMM20 as part of the TOM complex by showing that the Tom40 precursor forms its first stable intermediate with the outer face of the TOM complex. Correct component annotation. Reason: Correct. The study demonstrates the TOM complex in human cells and TOMM20 is a well-established component. Supporting Evidence: PMID:15644312 The precursor then forms its first stable intermediate with the outer face of the TOM complex before its membrane integration and assembly.
GO:0005515 protein binding	IPI PMID:14557246 AIP is a mitochondrial import mediator that binds to both im...	REMOVE	Summary: IPI annotation from PMID:14557246 (Yano et al. 2003), which showed that AIP binds to Tom20 and that both proteins bind mitochondrial preproteins. The binding between Tom20 and preproteins is specific to mitochondrial targeting sequences. "Protein binding" is uninformative and does not capture the specificity demonstrated in this paper. Reason: The interaction demonstrated is specific preprotein binding via mitochondrial targeting sequences, which is already captured by GO:0140436 "mitochondrial signal sequence receptor activity" (replacement for the obsolete GO:0030943). The generic "protein binding" annotation does not add functional information. Supporting Evidence: PMID:14557246 AIP as well as Tom20 binds specifically to mitochondrial preproteins [...] no or little binding of AIP and Tom20 to proteins destined for other organelles, including peroxisomes, ER, and nucleus, was observed.
GO:0005742 mitochondrial outer membrane translocase complex	TAS PMID:14557246 AIP is a mitochondrial import mediator that binds to both im...	ACCEPT	Summary: TAS annotation from PMID:14557246 (Yano et al. 2003). The paper describes Tom20 as part of the TOM complex, the preprotein translocase of the mitochondrial outer membrane. Correct component annotation. Reason: Correct. The paper confirms TOMM20 as a component of the TOM complex. Supporting Evidence: PMID:14557246 Preproteins with NH2-terminal presequences are initially recognized by the receptor Tom20, although preproteins with internal targeting signals such as carrier proteins are recognized preferentially by Tom70.
GO:0015450 protein-transporting ATPase activity	IDA PMID:14557246 AIP is a mitochondrial import mediator that binds to both im...	REMOVE	Summary: IDA annotation of TOMM20 to GO:0015450 "protein-transporting ATPase activity" from PMID:14557246. This is problematic. GO:0015450 describes "primary active carrier-mediated transport of a protein across a membrane, driven by the hydrolysis of the diphosphate bond of inorganic pyrophosphate, ATP, or another nucleoside triphosphate." TOMM20 does not have ATPase activity. It is a receptor that recognizes presequences. The TOM complex as a whole translocates proteins, but the driving force is primarily the membrane potential and mitochondrial Hsp70 (mtHsp70) pulling from the matrix side, not ATP hydrolysis by TOMM20 itself. TOMM20 has no known ATPase catalytic activity. This annotation appears to be a misattribution of the overall translocation mechanism to the receptor subunit. Reason: TOMM20 does not possess ATPase activity. It is a receptor subunit that recognizes presequences via its TPR-like binding groove. The energy for protein translocation across the outer membrane comes from the membrane potential and mtHsp70 ATPase activity in the matrix, not from TOMM20. There is no evidence in PMID:14557246 or any other publication that TOMM20 itself has ATPase activity. Supporting Evidence: PMID:35733257 Tom20, as the major import receptor, together with Tom70 and Tom22 target mitochondrial precursor proteins in the cytosol precisely
GO:0051082 unfolded protein binding	IDA PMID:14557246 AIP is a mitochondrial import mediator that binds to both im...	MARK AS OVER ANNOTATED	Summary: This annotation to GO:0051082 "unfolded protein binding" for TOMM20 is misleading and represents an over-annotation. The cited paper (Yano et al. 2003, PMID:14557246) is primarily about AIP (arylhydrocarbon receptor-interacting protein), not Tom20. The paper demonstrates that AIP is the protein with chaperone-like activity that suppresses thermal aggregation of substrate proteins and binds unfolded proteins. Tom20 is shown to bind mitochondrial preproteins via their N-terminal presequences (targeting signals), not based on their folding state. The binding groove of Tom20 recognizes the hydrophobic face of amphiphilic helical presequences through hydrophobic interactions, which is a signal sequence recognition function, not an unfolded protein sensing function. The paper explicitly states that Tom20 binds preproteins and non-mitochondrial proteins were not bound, demonstrating specificity for mitochondrial targeting signals rather than unfolded protein states per se. Furthermore, TOMM20 already had a more specific annotation to GO:0030943 "mitochondrion targeting sequence binding" (IDA from PMID:35733257 and IBA from GO_REF:0000033), whose receptor replacement is GO:0140436 "mitochondrial signal sequence receptor activity". The GO:0051082 term is now formally obsolete (go-ontology issue 30962) precisely because it conflates signal recognition with chaperone activity. TOMM20 is a protein import receptor, not a chaperone. Reason: TOMM20 does not function as an unfolded protein binding chaperone. The evidence in PMID:14557246 shows Tom20 recognizes mitochondrial presequences via hydrophobic interactions with the amphiphilic helical targeting signal. The paper states: "The binding groove of Tom20 mainly consists of a TPR and a glutamine-rich segment, and hydrophobic residues in the groove interact with the hydrophobic face of the amphiphilic helical presequence" and "AIP as well as Tom20 binds specifically to mitochondrial preproteins" while "no or little binding of AIP and Tom20 to proteins destined for other organelles" was observed. This demonstrates signal-specific recognition, not general unfolded protein binding. The chaperone-like aggregation suppression activity described in the paper belongs to AIP, not Tom20. TOMM20's signal-specific binding is captured by GO:0140436 "mitochondrial signal sequence receptor activity", the replacement for the now-obsolete GO:0030943. GO:0051082 is now formally obsolete (go-ontology#30962) because it conflates distinct molecular mechanisms. Proposed replacements: mitochondrial signal sequence receptor activity Supporting Evidence: PMID:14557246 The binding groove of Tom20 mainly consists of a TPR and a glutamine-rich segment, and hydrophobic residues in the groove interact with the hydrophobic face of the amphiphilic helical presequence. PMID:14557246 AIP as well as Tom20 binds specifically to mitochondrial preproteins [...] no or little binding of AIP and Tom20 to proteins destined for other organelles, including peroxisomes, ER, and nucleus, was observed. PMID:14557246 AIP was found to function as a chaperone to suppress thermal aggregation of rhodanese and citrate synthase (Fig. 6). AIP may function as a chaperone to maintain mitochondria-targeted preproteins unfolded and to suppress their aggregation. PMID:14557246 Preproteins with NH2-terminal presequences are initially recognized by the receptor Tom20, although preproteins with internal targeting signals such as carrier proteins are recognized preferentially by Tom70.
GO:0070585 protein localization to mitochondrion	IDA PMID:14557246 AIP is a mitochondrial import mediator that binds to both im...	ACCEPT	Summary: IDA annotation from PMID:14557246 (Yano et al. 2003). The paper demonstrates that Tom20 recognizes preproteins via their mitochondrial targeting sequences and is part of the TOM complex that facilitates protein import. GO:0070585 "protein localization to mitochondrion" is a broad process term that accurately describes the outcome of TOMM20 activity. While more specific terms like GO:0006626 "protein targeting to mitochondrion" or GO:0030150 "protein import into mitochondrial matrix" are also appropriate, this broader term is not incorrect. Reason: Correct. TOMM20 facilitates protein localization to the mitochondrion by recognizing mitochondrial targeting sequences. This is a core biological process for TOMM20. Supporting Evidence: PMID:14557246 Preproteins with NH2-terminal presequences are initially recognized by the receptor Tom20
GO:0005742 mitochondrial outer membrane translocase complex	NAS PMID:7498524 A human homolog of the mitochondrial protein import receptor...	ACCEPT	Summary: NAS annotation from PMID:7498524 (Seki et al. 1995), one of the original papers identifying human TOMM20 (then called Mom19 homolog). The paper showed that the human Mom19 homolog is targeted to yeast mitochondria and specifically associates with the outer membrane receptor complex. This was the original identification of human TOMM20 as a TOM complex component. Reason: Correct. This is the foundational paper identifying human TOMM20 as a component of the mitochondrial outer membrane translocase complex. Supporting Evidence: PMID:7498524 the human Mom19 homolog is targeted to isolated yeast mitochondria and specifically associates with the outer membrane receptor complex, suggesting that indeed a mitochondrial import receptor was identified.

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