STOML3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0008200 ion channel inhibitor activity	IBA GO_REF:0000033	MODIFY	Summary: The IBA annotation to ion channel inhibitor activity is phylogenetically inferred from the stomatin family but is overly restrictive. STOML3 functions as a bidirectional modulator of mechanosensitive ion channels rather than a simple inhibitor. It potentiates Piezo1/2 channels by lowering their activation threshold while modulating (including suppressing) ASIC gating properties. A more accurate term would be ion channel regulator activity (GO:0099106). Reason: STOML3 does not simply inhibit ion channels; it sensitizes Piezo channels to mechanical stimuli while modulating ASICs. The term "ion channel regulator activity" better captures its bidirectional modulatory function. Proposed replacements: ion channel regulator activity Supporting Evidence: DOI:10.1038/ncomms4520 Using neurons from knockout mice, we show that displacement thresholds increase by one order of magnitude in the absence of stomatin-like protein 3 (STOML3). DOI:10.1038/ncomms4520 Thus, the stomatin-domain proteins STOML1 and STOML3 have a potent effect in preventing short-term desensitization of Piezo currents dependent on prior mechanical stimulation. DOI:10.1098/rsob.120096 STOML3 directly interacts with multiple ASIC subunits (ASIC1a/1b/2a/2b/3/4) as shown by co-immunoprecipitation and FRET; interactions occur predominantly in a highly mobile vesicular compartment.
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Plasma membrane localization is well-supported by multiple lines of evidence. STOML3 is an integral membrane protein with a single transmembrane region that localizes to the plasma membrane in sensory neurons. Reason: Core localization supported by UniProt annotation and experimental evidence showing plasma membrane localization in DRG neurons. Supporting Evidence: file:human/STOML3/STOML3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Single-pass type III membrane protein. Note=Detected in lipid rafts. Reactome:R-HSA-8863494 STOML3 and stomatin are expressed by primary sensory neurons of the dorsal root ganglia (DRG) (Mannsfeldt et al. 1999, Wetzel et al. 2007) and regulate mechanoreceptor sensitivity in mice (Wetzel et al. 2007, Martinez-Saldago et al. 2007). file:human/STOML3/STOML3-deep-research-openai.md See deep research file for comprehensive analysis
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: Plasma membrane localization via combined automated annotation is consistent with other evidence sources. Reason: Computational inference consistent with experimental data and UniProt annotation. Supporting Evidence: file:human/STOML3/STOML3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Single-pass type III membrane protein.
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: General membrane annotation from InterPro domain mapping is accurate but less specific than plasma membrane. STOML3 is an integral membrane protein. Reason: Accurate general localization consistent with the stomatin domain architecture. Supporting Evidence: file:human/STOML3/STOML3-uniprot.txt Contains Band_7 domain (IPR001107) characteristic of membrane-associated stomatin family proteins.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: The IPI protein binding annotation comes from the HuRI high-throughput yeast two-hybrid interactome study. While the interactions detected (ADAM33, CLDN19, JAGN1, SEC22A, UPK2, ZDHHC24) are verified binary interactions from a systematic proteome-wide screen, they do not represent the physiologically relevant ion channel interactions that define STOML3 function. More informative would be annotations specifying interaction with Piezo channels and ASICs. Reason: The protein binding term is too general and uninformative about STOML3's specific function. The HuRI study detected binary interactions but these particular partners are not the mechanotransduction-relevant channels (Piezo1/2, ASICs) that represent STOML3's core function. Supporting Evidence: PMID:32296183 HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes.
GO:0005929 cilium	IEA GO_REF:0000107	ACCEPT	Summary: Cilium localization is inferred from mouse ortholog data. STOML3 has been detected in cilia of olfactory sensory neurons and motile cilia of respiratory epithelia. Reason: Consistent with reported expression in olfactory sensory neuron cilia and potential roles in ciliated cells. Supporting Evidence: file:human/STOML3/STOML3-deep-research-falcon.md Expression and physiological role of stomatin-domain proteins in the olfactory epithelium documented STOML3 localization in ciliated sensory neurons.
GO:0007165 signal transduction	IEA GO_REF:0000107	ACCEPT	Summary: Signal transduction annotation is accurate but general. STOML3 specifically modulates mechanosensory signaling by tuning ion channel activity in sensory neurons, converting mechanical stimuli into electrochemical signals. Reason: STOML3 is essential for mechanotransduction signaling in sensory neurons, modulating the conversion of mechanical force into neural signals. Supporting Evidence: DOI:10.1038/ncomms4520 Mouse stomatin-like protein 3 (STOML3) is a member of the stomatin-domain family of proteins that, like its Caenorhabditis elegans orthologue MEC-2, is required for normal mechano- transduction in touch receptors
GO:0045121 membrane raft	IEA GO_REF:0000107	ACCEPT	Summary: Membrane raft localization is well-supported. STOML3 binds cholesterol and partitions into cholesterol-rich lipid rafts where it organizes mechanotransduction complexes and stiffens local membrane mechanics. Reason: Core membrane organization function - STOML3 binding to cholesterol and localization in lipid rafts is essential for its mechanotransduction-modulating activity. Supporting Evidence: DOI:10.1038/ncomms9512 STOML3 is detected in cholesterol-rich lipid rafts. DOI:10.1038/ncomms9512 Here we show that this proline residue is also essential for the association between STOML3 and cholesterol-enriched lipid raft. file:human/STOML3/STOML3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Single-pass type III membrane protein. Note=Detected in lipid rafts.
GO:0005886 plasma membrane	IDA GO_REF:0000052	ACCEPT	Summary: Plasma membrane localization from HPA immunofluorescence data provides direct experimental evidence for this core localization. Reason: Direct experimental evidence (IDA) for plasma membrane localization. Supporting Evidence: GO_REF:0000052 Gene Ontology annotation based on curation of immunofluorescence data from the Human Protein Atlas.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8863494	ACCEPT	Summary: Plasma membrane localization from Reactome pathway curation documenting ASIC binding to STOML3 and stomatin at the plasma membrane. Reason: Reactome pathway annotation supporting plasma membrane localization in the context of ASIC channel binding. Supporting Evidence: Reactome:R-HSA-8863494 The function of STOML3 may be to prime the transduction complex for insertion into the plasma membrane (Lapatsina et al. 2012).
GO:0099106 ion channel regulator activity	IDA DOI:10.1038/ncomms4520	NEW	Summary: New annotation proposal based on direct experimental evidence showing STOML3 modulates Piezo channel activation thresholds. This is a core molecular function. Reason: STOML3's primary molecular function is to regulate mechanosensitive ion channel activity, specifically lowering Piezo1/2 activation thresholds and modulating ASIC gating. This is strongly supported by functional studies. Supporting Evidence: DOI:10.1038/ncomms4520 Using neurons from knockout mice, we show that displacement thresholds increase by one order of magnitude in the absence of stomatin-like protein 3 (STOML3). DOI:10.1038/ncomms4520 Structure–function experiments localize the Piezo modulatory activity of STOML3 to the stomatin domain, and higher-order scaffolds are a prerequisite for function. DOI:10.1098/rsob.120096 STOML3 and to a lesser extent STOM can modulate the gating of ASICs. STOML3 can bind ASIC1a, 1b, 2a, 2b, 3 and 4.
GO:0015485 cholesterol binding	IDA DOI:10.1038/ncomms9512	NEW	Summary: New annotation proposal for cholesterol binding, a key molecular function underlying STOML3's ability to organize membrane microdomains and stiffen membranes for mechanotransduction. Reason: Cholesterol binding is essential for STOML3 function - it enables membrane stiffening and organization of mechanotransduction complexes. This is directly demonstrated experimentally. Supporting Evidence: DOI:10.1038/ncomms9512 Here we show that stomatin-like protein-3 (STOML3) controls membrane mechanics by binding cholesterol and thus facilitates force transfer and tunes the sensitivity of mechano-gated channels, including Piezo channels. DOI:10.1038/ncomms9512 In mouse sensory neurons, depletion of cholesterol and deficiency of STOML3 similarly and interdependently attenuate mechanosensitivity while modulating membrane mechanics.
GO:0050982 detection of mechanical stimulus	IMP DOI:10.1038/ncomms4520	NEW	Summary: New annotation proposal for biological process involvement. STOML3 knockout mice show profound deficits in mechanosensation, with ~35-40% of mechanoreceptors becoming mechanically silent. Reason: STOML3 is essential for detection of mechanical stimuli in sensory neurons. Loss-of-function studies demonstrate requirement for mechanotransduction. Supporting Evidence: file:human/STOML3/STOML3-deep-research-falcon.md Stoml3 knockout leads to large-scale loss of mechanically sensitive mechanoreceptors (about 35-40% of mechanoreceptors become mechanically silent), elevated displacement thresholds in remaining units, and impaired tactile acuity in behavioral assays.
GO:0071260 cellular response to mechanical stimulus	IMP DOI:10.1038/ncomms4520	NEW	Summary: New annotation proposal for biological process involvement. STOML3 is essential for cellular responses to mechanical stimuli in sensory neurons, modulating ion channel activity in response to mechanical force. Reason: STOML3 modulates mechanosensitive ion channels in response to mechanical stimuli, representing a cellular response to mechanical stimulus. Loss-of-function studies demonstrate impaired mechanotransduction. Supporting Evidence: file:human/STOML3/STOML3-deep-research-falcon.md STOML3 lowers the activation threshold of Piezo1 and Piezo2 to ~10 nm displacements and is necessary for high sensitivity of mechanoreceptors.

Core Functions

STOML3 is a critical accessory protein that modulates mechanosensitive ion channel activity. It potentiates Piezo1 and Piezo2 channels by lowering their activation threshold from approximately 100 nm to approximately 10 nm displacements, enabling detection of molecular-scale movements relevant for fine touch. STOML3 also modulates ASIC gating properties. This modulatory activity requires the stomatin domain and higher-order oligomerization. STOML3 binds cholesterol and stiffens local membrane microdomains to facilitate force transfer to mechanotransducer channels.

Molecular Function:

ion channel regulator activity

Directly Involved In:

detection of mechanical stimulus cellular response to mechanical stimulus

Cellular Locations:

plasma membrane membrane raft

Supporting Evidence:

DOI:10.1038/ncomms4520
Using neurons from knockout mice, we show that displacement thresholds increase by one order of magnitude in the absence of stomatin-like protein 3 (STOML3).
DOI:10.1038/ncomms4520
Structure–function experiments localize the Piezo modulatory activity of STOML3 to the stomatin domain, and higher-order scaffolds are a prerequisite for function.
DOI:10.1038/ncomms9512
Here we show that stomatin-like protein-3 (STOML3) controls membrane mechanics by binding cholesterol and thus facilitates force transfer and tunes the sensitivity of mechano-gated channels, including Piezo channels.

STOML3 binds cholesterol via a conserved N-terminal motif, enabling its localization to cholesterol-rich membrane rafts. This cholesterol binding is essential for STOML3's mechanotransduction-modulating function, as it allows organization of specialized membrane microdomains that locally stiffen the membrane where mechanotransducer proteins reside, facilitating force transfer to ion channels.

Molecular Function:

cholesterol binding

Cellular Locations:

membrane raft

Supporting Evidence:

DOI:10.1038/ncomms9512
STOML3 is detected in cholesterol-rich lipid rafts.
DOI:10.1038/ncomms9512
In mouse sensory neurons, depletion of cholesterol and deficiency of STOML3 similarly and interdependently attenuate mechanosensitivity while modulating membrane mechanics.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Cyberian

Falcon

OpenAI

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