Q6IAA8 · LTOR1_HUMAN
- ProteinRagulator complex protein LAMTOR1
- GeneLAMTOR1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids161 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Key component of the Ragulator complex, a multiprotein complex involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:20381137, PubMed:22980980, PubMed:29158492).
Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it 1 acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and 2 mediates recruitment of Rag GTPases to the lysosome membrane (PubMed:22980980, PubMed:28935770, PubMed:29158492, PubMed:30181260, PubMed:31001086, PubMed:32686708, PubMed:36476874).
Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:20381137, PubMed:22980980, PubMed:29158492).
LAMTOR1 is directly responsible for anchoring the Ragulator complex to the lysosomal membrane (PubMed:31001086, PubMed:32686708).
LAMTOR1 wraps around the other subunits of the Ragulator complex to hold them in place and interacts with the Rag GTPases, thereby playing a key role in the recruitment of the mTORC1 complex to lysosomes (PubMed:28935770, PubMed:29107538, PubMed:29123114, PubMed:29285400).
Also involved in the control of embryonic stem cells differentiation via non-canonical RagC/RRAGC and RagD/RRAGD activation: together with FLCN, it is necessary to recruit and activate RagC/RRAGC and RagD/RRAGD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By similarity).
Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes (PubMed:20381137, PubMed:22980980).
May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes (PubMed:20544018).
May also play a role in RHOA activation (PubMed:19654316).
Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it 1 acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and 2 mediates recruitment of Rag GTPases to the lysosome membrane (PubMed:22980980, PubMed:28935770, PubMed:29158492, PubMed:30181260, PubMed:31001086, PubMed:32686708, PubMed:36476874).
Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:20381137, PubMed:22980980, PubMed:29158492).
LAMTOR1 is directly responsible for anchoring the Ragulator complex to the lysosomal membrane (PubMed:31001086, PubMed:32686708).
LAMTOR1 wraps around the other subunits of the Ragulator complex to hold them in place and interacts with the Rag GTPases, thereby playing a key role in the recruitment of the mTORC1 complex to lysosomes (PubMed:28935770, PubMed:29107538, PubMed:29123114, PubMed:29285400).
Also involved in the control of embryonic stem cells differentiation via non-canonical RagC/RRAGC and RagD/RRAGD activation: together with FLCN, it is necessary to recruit and activate RagC/RRAGC and RagD/RRAGD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By similarity).
Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes (PubMed:20381137, PubMed:22980980).
May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes (PubMed:20544018).
May also play a role in RHOA activation (PubMed:19654316).
GO annotations
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameRagulator complex protein LAMTOR1
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ6IAA8
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Lysosome membrane ; Lipid-anchor
Late endosome membrane ; Lipid-anchor
Note: Recruited to lysosome and endosome membranes through N-terminal myristoylation and palmitoylation.
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 2 | Abolished N-myristoylation and subsequent palmitoylation. | ||||
Sequence: G → A | ||||||
Mutagenesis | 3 | Decreased palmitoylation. | ||||
Sequence: C → A | ||||||
Mutagenesis | 3 | Does not affect interaction with ZDHHC3. | ||||
Sequence: C → S | ||||||
Mutagenesis | 3-4 | Abolished palmitoylation and recruitment to lysosomes, leading to impaired activation of the mTORC1 complex. | ||||
Sequence: CC → SS | ||||||
Mutagenesis | 4 | Decreased palmitoylation. | ||||
Sequence: C → A | ||||||
Mutagenesis | 4 | Does not affect interaction with ZDHHC3. | ||||
Sequence: C → S | ||||||
Natural variant | VAR_030250 | 73 | in dbSNP:rs1053443 | |||
Sequence: S → L | ||||||
Mutagenesis | 119 | Impaired assembly of the Ragulator complex. | ||||
Sequence: L → R | ||||||
Mutagenesis | 132 | Impaired assembly of the Ragulator complex. | ||||
Sequence: V → D | ||||||
Mutagenesis | 148-149 | Impaired assembly of the Ragulator complex. | ||||
Sequence: VD → AA | ||||||
Mutagenesis | 151-153 | Impaired recruiment of Rag GTPases (RRAGA and RRAGC) to the lysosomal membrane. | ||||
Sequence: KEE → AAA | ||||||
Mutagenesis | 154-156 | Impaired recruiment of Rag GTPases (RRAGA and RRAGC) to the lysosomal membrane. | ||||
Sequence: LVV → AAA | ||||||
Mutagenesis | 154-158 | Does not affect interaction with RRAGA and RRAGC in vitro. | ||||
Sequence: LVVQF → DDDQD |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 148 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for initiator methionine, lipidation, chain, cross-link, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Initiator methionine | 1 | UniProt | Removed | ||||
Sequence: M | |||||||
Lipidation | 2 | UniProt | N-myristoyl glycine | ||||
Sequence: G | |||||||
Chain | PRO_0000274292 | 2-161 | UniProt | Ragulator complex protein LAMTOR1 | |||
Sequence: GCCYSSENEDSDQDREERKLLLDPSSPPTKALNGAEPNYHSLPSARTDEQALLSSILAKTASNIIDVSAADSQGMEQHEYMDRARQYSTRLAVLSSSLTHWKKLPPLPSLTSQPHQVLASEPIPFSDLQQVSRIAAYAYSALSQIRVDAKEELVVQFGIP | |||||||
Lipidation | 3 | UniProt | S-palmitoyl cysteine | ||||
Sequence: C | |||||||
Lipidation | 4 | UniProt | S-palmitoyl cysteine | ||||
Sequence: C | |||||||
Cross-link | 20 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 26 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 27 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 27 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 30 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Cross-link | 31 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 40 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 42 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 42 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 45 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 48 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 55 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 56 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 56 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Cross-link | 60 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 61 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 63 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 73 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 96 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 97 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 98 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 98 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 100 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Cross-link | 103 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Cross-link | 104 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 110 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 113 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 138 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue (large scale data) | 140 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 141 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 141 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 144 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
N-terminal myristoylation and palmitoylation mediates its recruitment to lysosome membranes, thereby promoting localization of the Ragulator complex to lysosomes (PubMed:31001086).
N-myristoylation by NMT1 is required for palmitoylation at Cys-3 and Cys-4 (PubMed:34999170).
May be palmitoylated by ZDHHC3 (PubMed:35893977).
N-myristoylation by NMT1 is required for palmitoylation at Cys-3 and Cys-4 (PubMed:34999170).
May be palmitoylated by ZDHHC3 (PubMed:35893977).
Ubiquitinated at Lys-60, Lys-103 and Lys-104 by UBE3A, promoting its degradation by the proteasome (PubMed:30020076).
Ubiquitination at Lys-20 impairs the association with the lysosomal V-ATPase complex (PubMed:36476874).
Deubiquitination at Lys-20 by USP32 promotes the association with the lysosomal V-ATPase complex and subsequent activation of the mTORC1 complex (PubMed:36476874).
Ubiquitination at Lys-20 impairs the association with the lysosomal V-ATPase complex (PubMed:36476874).
Deubiquitination at Lys-20 by USP32 promotes the association with the lysosomal V-ATPase complex and subsequent activation of the mTORC1 complex (PubMed:36476874).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Induction
Down-regulated by cholesterol (at protein level).
Gene expression databases
Organism-specific databases
Interaction
Subunit
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980, PubMed:28935770, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:29285400, PubMed:31601708, PubMed:32868926, PubMed:35338845, PubMed:36103527, PubMed:36697823).
LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980).
Interacts with LAMTOR2 and LAMTOR3; the interaction is direct (PubMed:20381137, PubMed:22980980).
The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and RagD/RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:22980980, PubMed:32868926).
The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:22980980, PubMed:25561175, PubMed:25567906).
Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (PubMed:31672913, PubMed:31704029).
Associates with the lysosomal V-ATPase complex; interaction promotes the guanine nucleotide exchange factor (GEF) of the Ragulator complex (PubMed:36476874).
Interacts with MMP14 (PubMed:19654316).
Interacts with CDKN1B; prevents the interaction of CDKN1B with RHOA leaving RHOA in a form accessible to activation by ARHGEF2 (PubMed:19654316).
Interacts with PIP4P1 (PubMed:29644770).
LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980).
Interacts with LAMTOR2 and LAMTOR3; the interaction is direct (PubMed:20381137, PubMed:22980980).
The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and RagD/RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:22980980, PubMed:32868926).
The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:22980980, PubMed:25561175, PubMed:25567906).
Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator (PubMed:31672913, PubMed:31704029).
Associates with the lysosomal V-ATPase complex; interaction promotes the guanine nucleotide exchange factor (GEF) of the Ragulator complex (PubMed:36476874).
Interacts with MMP14 (PubMed:19654316).
Interacts with CDKN1B; prevents the interaction of CDKN1B with RHOA leaving RHOA in a form accessible to activation by ARHGEF2 (PubMed:19654316).
Interacts with PIP4P1 (PubMed:29644770).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q6IAA8 | CHAT P28329-3 | 3 | EBI-715385, EBI-25837549 | |
BINARY | Q6IAA8 | CTAG1B P78358 | 3 | EBI-715385, EBI-1188472 | |
BINARY | Q6IAA8 | FGFR3 P22607 | 3 | EBI-715385, EBI-348399 | |
BINARY | Q6IAA8 | GSN P06396 | 3 | EBI-715385, EBI-351506 | |
BINARY | Q6IAA8 | LAMTOR2 Q9Y2Q5 | 23 | EBI-715385, EBI-2643704 | |
BINARY | Q6IAA8 | LAMTOR3 Q9UHA4 | 17 | EBI-715385, EBI-1038192 | |
BINARY | Q6IAA8 | LAMTOR4 Q0VGL1 | 13 | EBI-715385, EBI-5658976 | |
BINARY | Q6IAA8 | PECAM1 P16284 | 3 | EBI-715385, EBI-716404 | |
BINARY | Q6IAA8 | Q9Y649 | 3 | EBI-715385, EBI-25900580 | |
BINARY | Q6IAA8 | RAB5A P20339 | 3 | EBI-715385, EBI-399437 | |
BINARY | Q6IAA8 | RRAGA Q7L523 | 15 | EBI-715385, EBI-752376 | |
BINARY | Q6IAA8 | RRAGC Q9HB90 | 21 | EBI-715385, EBI-752390 | |
BINARY | Q6IAA8 | SLC38A9 Q8NBW4 | 15 | EBI-715385, EBI-9978316 | |
BINARY | Q6IAA8 | UBE2K P61086 | 3 | EBI-715385, EBI-473850 | |
BINARY | Q6IAA8 | UBQLN1 Q9UMX0 | 3 | EBI-715385, EBI-741480 | |
BINARY | Q6IAA8 | VIM P08670 | 3 | EBI-715385, EBI-353844 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-43 | Disordered | ||||
Sequence: MGCCYSSENEDSDQDREERKLLLDPSSPPTKALNGAEPNYHSL | ||||||
Compositional bias | 9-24 | Basic and acidic residues | ||||
Sequence: NEDSDQDREERKLLLD | ||||||
Region | 121-161 | Interaction with LAMTOR2 and LAMTOR3 | ||||
Sequence: SEPIPFSDLQQVSRIAAYAYSALSQIRVDAKEELVVQFGIP |
Sequence similarities
Belongs to the LAMTOR1 family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length161
- Mass (Da)17,745
- Last updated2007-02-06 v2
- Checksum610CC6C548356051
Computationally mapped potential isoform sequences
There are 5 potential isoforms mapped to this entry
Features
Showing features for compositional bias, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 9-24 | Basic and acidic residues | ||||
Sequence: NEDSDQDREERKLLLD | ||||||
Sequence conflict | 50 | in Ref. 2; CAG33528 | ||||
Sequence: E → V | ||||||
Sequence conflict | 60 | in Ref. 1; AAL55767 | ||||
Sequence: K → R | ||||||
Sequence conflict | 69 | in Ref. 2; CAG33528 | ||||
Sequence: S → P |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF289583 EMBL· GenBank· DDBJ | AAL55767.1 EMBL· GenBank· DDBJ | mRNA | ||
CR457247 EMBL· GenBank· DDBJ | CAG33528.1 EMBL· GenBank· DDBJ | mRNA | ||
AK000632 EMBL· GenBank· DDBJ | BAA91297.1 EMBL· GenBank· DDBJ | mRNA | ||
BC001706 EMBL· GenBank· DDBJ | AAH01706.1 EMBL· GenBank· DDBJ | mRNA |