STOML1 (Stomatin-like protein 1, also known as SLP-1) is a monotopic membrane protein belonging to the SPFH/band-7 family with a distinctive bipartite architecture: an N-terminal stomatin-like (SPFH) domain and a C-terminal sterol carrier protein-2 (SCP-2) domain. Unlike stomatin which localizes predominantly to the plasma membrane, STOML1 is targeted to late endosomes/multivesicular bodies via an N-terminal GYXXF sorting signal. The protein plays roles in cholesterol/lipid transfer within endolysosomal membranes, modulation of acid-sensing ion channels (ASICs) in sensory neurons, and regulation of F-box protein FBXW7 stability. STOML1 interacts with stomatin, redistributing it from plasma membrane to late endosomes, associates with the lysosomal cation channel TRPML1, and binds FBXW7-gamma and CDK2 to regulate protein turnover. Expression is highest in brain, heart, and skeletal muscle, with functional significance in neuronal proton sensing.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008200 ion channel inhibitor activity | IBA GO_REF:0000033 | ACCEPT | Summary: STOML1 has been experimentally demonstrated to inhibit acid-sensing ion channels (ASICs), specifically strongly inhibiting ASIC1a-mediated proton currents and accelerating ASIC3 inactivation. The SCP-2 domain is required for ASIC1a modulation. STOML1 knockout mice show larger proton-gated currents in dorsal root ganglion neurons, confirming an endogenous inhibitory function (file:human/STOML1/STOML1-deep-research-falcon.md). Reason: This IBA annotation is strongly supported by experimental evidence. The annotation accurately reflects the core molecular function of STOML1 in inhibiting acid-sensing ion channels (ASICs). GO:0008200 (ion channel inhibitor activity) is appropriate as STOML1 inhibits ASIC1a current amplitude and accelerates ASIC3 inactivation. Supporting Evidence: file:human/STOML1/STOML1-deep-research-falcon.md STOML1 modulates acid-sensing ion channels (ASICs) in sensory neurons. It strongly inhibits ASIC1a-mediated proton currents and accelerates ASIC3 inactivation, with no inhibition of ASIC2a. The SCP-2 domain is necessary for ASIC1a modulation. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: While STOML1 does localize to the plasma membrane in neurons where it modulates ASICs, experimental evidence shows that STOML1 primarily localizes to late endosomes/multivesicular bodies, not the plasma membrane. Wild-type STOML1 was never observed at significant plasma membrane levels in steady state; only when the N-terminal GYXXF sorting signal was mutated did STOML1 relocate to the plasma membrane (PMID:19696025). Reason: The IBA annotation suggesting plasma membrane localization may be inherited from other stomatin family members. While STOML1 may transit through or function at the plasma membrane in certain contexts (particularly for ASIC modulation in neurons), its predominant steady-state localization is to late endosomes. This annotation is acceptable as non-core but late endosome membrane (GO:0031902) is more representative of STOML1's primary localization. Supporting Evidence: PMID:19696025 We show here that SLP-1 localizes to the late endosomal compartment, like stomatin. Unlike stomatin, SLP-1 does not localize to the plasma membrane. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: This IEA annotation suggesting plasma membrane localization is less accurate than late endosome membrane for STOML1. Experimental evidence clearly shows STOML1 localizes to late endosomes/multivesicular bodies as its primary location. Plasma membrane localization only occurs when the N-terminal sorting signal is mutated. Reason: This is a computational annotation that is broader than the experimentally determined primary localization. While not incorrect (STOML1 may function at plasma membrane in neurons for ASIC modulation), the primary localization is to late endosomes. Accept as non-core since it represents a secondary or transient localization. Supporting Evidence: PMID:19696025 We show here that SLP-1 localizes to the late endosomal compartment, like stomatin. Unlike stomatin, SLP-1 does not localize to the plasma membrane. |
| GO:0006869 lipid transport | IEA GO_REF:0000043 | ACCEPT | Summary: STOML1 contains an SCP-2 (sterol carrier protein-2) domain, which is implicated in cholesterol and lipid transfer. Under conditions of blocked cholesterol efflux from late endosomes, STOML1 expression induces enlarged, cholesterol-filled vesicles, and this phenotype requires the SCP-2 domain (PMID:19696025). This strongly supports a role in lipid/sterol transport. Reason: This IEA annotation based on UniProt keyword mapping is well-supported by experimental evidence showing STOML1's SCP-2 domain is involved in cholesterol handling at late endosomes. The annotation reflects a core function of STOML1 in lipid/sterol transfer. Supporting Evidence: PMID:19696025 In accordance with the proposed lipid transfer function, we show that, under conditions of blocked cholesterol efflux from late endosomes, SLP-1 induces the formation of enlarged, cholesterol-filled, weakly LAMP-2-positive, acidic vesicles in the perinuclear region. This massive cholesterol accumulation clearly depends on the SCP-2 domain of SLP-1, suggesting a role for this domain in cholesterol transfer to late endosomes. |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: STOML1 is indeed a membrane protein with a single transmembrane helix (type III membrane protein). This general membrane annotation is correct but very broad. Reason: This is a correct but generic annotation. STOML1 is a monotopic membrane protein that associates with detergent-resistant membranes (lipid rafts). The annotation is accurate though more specific terms (late endosome membrane, membrane raft) are more informative. Supporting Evidence: PMID:19696025 The human stomatin-like protein-1 (SLP-1) is a membrane protein with a characteristic bipartite structure containing a stomatin domain and a sterol carrier protein-2 (SCP-2) domain. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000120 | ACCEPT | Summary: STOML1 localizes to late endosomes/multivesicular bodies, which are cytoplasmic vesicles. The protein also appears in small extracellular vesicle proteomes, consistent with its endolysosomal localization. Reason: This annotation is consistent with STOML1's localization to multivesicular bodies and late endosomes, which are indeed cytoplasmic vesicles. The annotation is accurate though the more specific term GO:0031902 (late endosome membrane) is preferred. Supporting Evidence: PMID:19696025 expressed SLP-1 was always identified in perinuclear vesicles that co-localized with markers for the late endosomal/lysosomal compartment. Late endosomal targeting was further supported by immunoelectron microscopy and co-localization with acidic vesicles and endocytosed TRITC-dextran. |
| GO:0031902 late endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: This is the most accurate cellular component annotation for STOML1. Experimental evidence from confocal microscopy, immuno-EM, and co-localization studies shows STOML1 localizes to late endosomes/multivesicular bodies, co-localizing with LAMP-2, Rab7, and Rab9 but not early endosome markers (PMID:19696025). Reason: This annotation accurately represents STOML1's primary subcellular localization. The N-terminal GYXXF sorting signal directs STOML1 specifically to late endosomes, and mutation of this signal results in plasma membrane localization instead. This is a core annotation for STOML1. Supporting Evidence: PMID:19696025 We show here that SLP-1 localizes to the late endosomal compartment, like stomatin. PMID:19696025 We found that the targeting of SLP-1 to late endosomes is caused by a GYXXPhi (Phi being a bulky, hydrophobic amino acid) sorting signal at the N terminus. Mutation of this signal results in plasma membrane localization. |
| GO:0045121 membrane raft | IEA GO_REF:0000044 | ACCEPT | Summary: STOML1 associates with detergent-resistant membranes (lipid rafts), similar to other stomatin family members. The PHB domain is involved in this association, possibly in combination with the hydrophobic domain (PMID:19696025). Reason: This annotation is experimentally supported. STOML1 associates with detergent-resistant membranes and its distribution in density gradients resembles that of stomatin and cholesterol. This is a core characteristic of SPFH/stomatin family proteins. Supporting Evidence: PMID:19696025 SLP-1 and stomatin co-localize in the late endosomal compartment, they co-immunoprecipitate, thus showing a direct interaction, and they associate with detergent-resistant membranes. PMID:19696025 SLP-1 is partially associated with DRMs and its distribution resembles that of stomatin and cholesterol. |
| GO:0005515 protein binding | IPI PMID:19696025 Stomatin-like protein-1 interacts with stomatin and is targe... | ACCEPT | Summary: PMID:19696025 demonstrates that STOML1 interacts directly with stomatin via co-immunoprecipitation. The interaction site was localized to the conserved stomatin part of STOML1. Overexpression of STOML1 redistributes stomatin from the plasma membrane to late endosomes. Reason: While GO:0005515 (protein binding) is too generic and uninformative, the interaction with stomatin is experimentally validated. The specific interaction partner is stomatin (STOM). Accepting this annotation as the interaction is well-documented, though a more specific term would be preferable if one existed. Supporting Evidence: PMID:19696025 Overexpression of SLP-1 leads to the redistribution of stomatin from the plasma membrane to late endosomes suggesting a complex formation between these proteins. PMID:19696025 We proved the postulated interaction of SLP-1 with stomatin by co-immunoprecipitation and localized the interaction site to the conserved stomatin part of SLP-1. |
| GO:0005515 protein binding | IPI PMID:23082202 The stomatin-like protein SLP-1 and Cdk2 interact with the F... | ACCEPT | Summary: PMID:23082202 demonstrates that STOML1 (SLP-1) interacts with FBXW7-gamma isoform and CDK2 via co-immunoprecipitation. The interaction with FBXW7-gamma is specific (not seen with alpha or beta isoforms) and STOML1 overexpression inhibits FBXW7-gamma degradation. Reason: While GO:0005515 (protein binding) is generic, the study demonstrates specific interactions with FBXW7 (isoform gamma) and CDK2. These are novel interaction partners that may be relevant to STOML1's role in cell cycle regulation. The annotation is accepted as it represents validated protein-protein interactions. Supporting Evidence: PMID:23082202 We have identified a novel interaction partner called SLP-1 that binds the unique N-terminal domain of Fbw7-gamma and inhibits its degradation when overexpressed. PMID:23082202 We demonstrate that Cdk2 also binds the N-terminal domain of Fbw7-gamma as well as SLP-1. |
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Download this section (compressed HTML)Q: What is the functional significance of STOML1's interaction with TRPML1 at lysosomes? Does it regulate lysosomal calcium signaling or autophagosome-lysosome fusion?
Q: How does STOML1 modulate ASICs when its primary localization is to late endosomes rather than the plasma membrane? Is there regulated trafficking to the cell surface in neurons?
Q: What is the physiological relevance of the STOML1-FBXW7-CDK2 interaction network in cell cycle regulation?
Experiment: Generate tissue-specific STOML1 knockout mice to assess the role of STOML1 in sensory neuron function and pain perception.
Hypothesis: STOML1 knockout will result in enhanced acid sensitivity and altered pain responses
Experiment: Perform live-cell imaging to track STOML1 trafficking between late endosomes and plasma membrane in neurons.
Hypothesis: STOML1 may transiently localize to plasma membrane for ASIC modulation before recycling to late endosomes
Experiment: Investigate whether STOML1 interacts with and regulates TRPML1 activity using electrophysiology and calcium imaging in STOML1 knockout cells.
Hypothesis: STOML1 may modulate lysosomal calcium release through interaction with TRPML1
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