| 2000 |
Crystal structure of the VHS domain of human TOM1 resolved to 1.5 Å, revealing eight helices in a superhelix with a basic patch on helix 3 and a negatively charged ridge on helix 2; conserved surfaces on helices 2 and 4 mediate protein-protein interactions, and the positively charged helix 3 surface is proposed to mediate membrane binding. |
X-ray crystallography (1.5 Å resolution) |
Biochemistry |
High |
10985773
|
| 2003 |
TOM1 directly binds ubiquitin chains and Tollip, forming an endogenous complex (confirmed by gel filtration and Western blot); TOM1 also binds clathrin heavy chain through a clathrin-binding motif, and GFP-TOM1 localization in cytoplasm depends on this clathrin-binding motif. |
Co-immunoprecipitation, gel filtration, GST pulldown, fluorescence microscopy |
The Journal of biological chemistry |
High |
14563850
|
| 2004 |
The GAT domain of TOM1 binds both ubiquitin and Tollip at an overlapping, mutually exclusive site; Tollip localizes to early endosomes and recruits cytosolic TOM1 and ubiquitinated proteins to endosomes; Tom1L1 shares these interactions. |
GST pulldown, co-immunoprecipitation, fluorescence microscopy, mutagenesis |
The Journal of biological chemistry |
High |
15047686
|
| 2003 |
Endofin, a FYVE-domain early endosomal protein, directly binds the C-terminal region of TOM1 (confirmed by GST pulldown and co-IP); endofin overexpression recruits cytosolic TOM1 to endosomes, identifying TOM1 as an endofin effector. |
Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence, sucrose gradient fractionation |
The Journal of biological chemistry |
High |
14613930
|
| 2005 |
TOM1 recruits clathrin to early endosomes via its C-terminal clathrin-binding sites (residues 300–321, 321–326, and LEDEF motif at 362–366); endofin exploits this TOM1–clathrin interaction to specifically recruit clathrin (not dynamin or AP complexes) onto endosomes; microinjection of TOM1 antibody reduces membrane-associated clathrin. |
Mutagenesis, co-immunoprecipitation, overexpression, microinjection, immunofluorescence |
Journal of cell science |
High |
15657082
|
| 2006 |
Tom1L1 and Tom1L2 also interact with Tollip via their GAT domains and recruit clathrin to endosomes via their C-terminal regions when coexpressed with Tollip, demonstrating a conserved function of the TOM1 family in clathrin recruitment to endosomes. |
Co-immunoprecipitation, fluorescence microscopy |
Biochemical and biophysical research communications |
Medium |
16412388
|
| 2004 |
Tom1 overexpression suppresses NF-κB and AP-1 activation induced by IL-1β or TNF-α; the VHS domain is required for this suppressive activity, identifying TOM1 as a negative regulator of IL-1β– and TNF-α–induced signaling. |
Reporter gene (luciferase) assay, overexpression, domain deletion analysis |
Biological & pharmaceutical bulletin |
Medium |
15056867
|
| 2012 |
Myosin VI, together with its adaptor proteins NDP52, optineurin, T6BP, and TOM1, is required for autophagosome maturation and autophagosome–lysosome fusion; TOM1 is identified as a myosin VI binding partner on endosomes, and loss of myosin VI or TOM1 blocks delivery of endocytic cargo to autophagosomes and prevents autophagosome–lysosome fusion. |
Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy, autophagy flux assays |
Nature cell biology |
High |
23023224
|
| 2010 |
miR-126 directly targets the 3′-UTR of TOM1 mRNA to suppress TOM1 protein levels; TOM1 overexpression downregulates NF-κB–driven IL-8 secretion, while TOM1 knockdown increases IL-8 secretion after LPS or IL-1β stimulation, placing TOM1 as a negative regulator of TLR2/4 and IL-1 signaling. |
Luciferase 3′-UTR reporter assay, miRNA mimic transfection, siRNA knockdown, NF-κB reporter assay, ELISA |
Journal of immunology |
High |
20083669
|
| 2015 |
TOM1 directly binds phosphatidylinositol 5-monophosphate (PI5P); the interaction is mediated by a specific domain of TOM1; PI5P-dependent recruitment of TOM1 to signaling endosomes delays EGFR degradation and inhibits bulk fluid-phase endocytosis, identifying TOM1 as a PI5P effector that impedes endosomal maturation. |
Lipid-binding assays, protein-lipid overlay, siRNA knockdown, overexpression, EGFR degradation assay, endocytosis assay |
Journal of cell science |
High |
25588840
|
| 1999 |
Yeast Tom1 encodes a ~380 kDa HECT-domain E3 ubiquitin ligase; the conserved cysteine in the HECT domain is required for ubiquitin thioester formation and for Tom1 function; loss of the HECT domain or the entire gene causes temperature-sensitive growth with defects in nuclear division, nucleolar integrity, and nucleocytoplasmic transport. |
Site-directed mutagenesis of catalytic Cys, ubiquitin conjugation assay (GST-HECT overexpression), electron microscopy, immunofluorescence, FISH |
Gene |
High |
10395901
|
| 2012 |
Yeast HECT E3 ligase Tom1 is required for Cdc6 degradation during G1 phase of the cell cycle, acting independently of SCF(Cdc4); Tom1 directly immunoprecipitates Cdc6 via a C-terminal region of Cdc6; loss of Tom1 reduces Cdc6 ubiquitination and causes aberrant chromatin association of Cdc6 and Mcm4 in G1. |
Genetic epistasis, ubiquitination assay, co-immunoprecipitation, cell cycle analysis |
The Journal of biological chemistry |
High |
23129771
|
| 2012 |
Yeast HECT E3 ligase Tom1 is required for cell-cycle-regulated degradation of the F-box protein Dia2 during G1 and G2/M; Tom1 binding to Dia2 is enhanced in G1 and reduced in S phase; Tom1 recognizes positively charged residues in the Dia2 degradation/NLS domain; loss of Dia2 partially suppresses tom1 temperature-sensitive growth and G1-to-S delay. |
Genetic epistasis, co-immunoprecipitation, cell cycle synchronization, ubiquitination assay, mutagenesis |
Molecular biology of the cell |
High |
22933573
|
| 2018 |
Yeast HECT E3 ligase Tom1 directly interacts with and promotes the degradation of Spo12 (a FEAR network component) specifically in G2/M phase; overexpression of Spo12 is cytotoxic in the absence of Tom1. |
Co-immunoprecipitation, protein stability assay, genetic overexpression |
FEBS letters |
Medium |
29683484
|
| 2017 |
Yeast Tom1 E3 ubiquitin ligase associates with aberrant nascent peptides targeted by the ribosome-bound quality control (RQC) complex; Tom1 interacts with the light (ribosome-unbound) RQC complex and limits accumulation and aggregation of aberrant peptides independently of its E3 ligase catalytic activity. |
Co-immunoprecipitation, genetic epistasis, protein aggregation assay, cell fractionation |
Molecular biology of the cell |
Medium |
28298488
|
| 2025 |
Cryo-EM structures of yeast Tom1 during active ubiquitination reveal that a non-canonical ubiquitin-binding site in the solenoid domain coordinates a 'structural ubiquitin' that contributes to K48 poly-ubiquitin chain specificity; the extended domain architecture beyond the catalytic HECT module directly contributes to catalytic fidelity. |
Cryo-EM, in vitro ubiquitination assay, mutagenesis |
Cell reports |
High |
40359109
|
| 2008 |
Dictyostelium DdTom1, the sole VHS-domain protein in Dictyostelium, has a GAT domain that binds ubiquitin and a C-terminal domain that recruits clathrin, EPS15, and TSG101 (an ESCRT-I component); both VHS and GAT domains bind phospholipids, enabling endosomal membrane recruitment; DdTom1 is proposed to constitute an ancestral ESCRT-0 complex. |
GST pulldown, co-immunoprecipitation, lipid-binding assays, fluorescence microscopy |
Traffic |
Medium |
19054384
|
| 2018 |
TOM1 binds FcγRIIb2 and represses its recycling, thereby attenuating neuronal uptake of oligomeric Aβ1-42; TOM1 expression is downregulated in AD hippocampus and 3xTg-AD mice; lentiviral TOM1 overexpression rescues memory impairment in 3xTg-AD mice. |
Co-immunoprecipitation, knockdown/overexpression, lentiviral gene delivery, behavioral assays, KO mouse studies |
The Journal of neuroscience |
Medium |
30185465
|
| 2019 |
The TOM1 G307D disease variant fails to interact with TOLLIP; patient-derived cells show impaired autophagy and enhanced susceptibility to apoptosis, reduced STAT and ERK1/2 signaling, and poor IFN-γ and IL-17 secretion, linking the TOM1–TOLLIP interaction to immune regulation. |
Whole-exome sequencing, co-immunoprecipitation, patient cell functional assays (autophagy flux, signaling, cytokine secretion) |
NPJ genomic medicine |
Medium |
31263572
|
| 2019 |
The TOM1 VHS domain preferentially binds PI5P via two non-cooperative binding sites involving acyl chains; PI5P binding destabilizes the VHS domain structure (reduced thermostability, interhelical contacts, and compaction), mechanistically explaining how PI5P causes TOM1 to adopt a different conformational state that could alter downstream effector interactions. |
Thermal denaturation (DSF), isothermal calorimetry (ITC), NMR, CD spectroscopy |
Scientific reports |
Medium |
31350523
|
| 2024 |
SIRT5 directly interacts with TOM1 and desuccinylates it at K48, stabilizing TOM1 protein; TOM1 knockdown reverses SIRT5-mediated promotion of autophagy and inhibition of apoptosis in a hypoxia/reoxygenation MIRI cell model, placing TOM1 downstream of SIRT5 in autophagy regulation. |
Co-immunoprecipitation, succinylation assay, siRNA knockdown, overexpression, autophagy assays, in vivo MI model |
BMC cardiovascular disorders |
Medium |
39210272
|
| 2023 |
SENP1 alleviates CIH-induced neuroinflammation by de-SUMOylating TOM1, thereby stabilizing TOM1 and promoting microglial migration; SENP1 knockout enhances TOM1 SUMOylation, inhibits microglial migration, and worsens neuroinflammation and Aβ42 deposition. |
SENP1 overexpression/KO, SUMOylation assay, siRNA knockdown, in vitro and in vivo CIH models |
International immunopharmacology |
Medium |
37137262
|
| 2025 |
The TOM1 G307D variant impairs TOM1–TOLLIP interaction; TOM1 normally reduces TOLLIP's PI(3)P binding (confirmed biophysically), committing TOLLIP to cargo trafficking; G307D patient cells show accumulated autophagosomes due to defective autophagosome–lysosome fusion and excessive activation of inflammatory pathways. |
Biophysical binding assays (ITC/SPR), co-immunoprecipitation, patient cell autophagy flux assays, lipid-binding assays |
Disease models & mechanisms |
High |
40936361
|
| 2024 |
An internal linker region adjacent to the TOM1 VHS domain enhances ubiquitin-binding affinity and is modulated by phosphorylation; TOM1's PI5P binding is pH-dependent (as is TOLLIP's), and under acidic endosomal conditions TOM1 retains TOLLIP binding but loses ubiquitin binding, suggesting pH-sensing regulates cargo commitment versus PI5P-dependent signaling. |
NMR, ITC, mutagenesis, phosphorylation assays, pH-titration binding assays |
Structure |
Medium |
39208792
|