Target of rapamycin complex subunit LST8 (MLST8)

The protein contains 326 amino acids for an estimated molecular weight of 35876 Da.

 

Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphoryla (updated: April 1, 2015)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete		TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.
Protein sequence (FASTA)
Protein coevolution profile (FreeContact)
Multiple Sequence Alignment (Muscle)

Interpro domains
Total structural coverage: 100%
Model score: 100
MODL_I-TASSER-3.0

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The reference OMIM entry for this protein is 612190

Mtor-associated protein lst8; mlst8
G-beta-like protein; gbl
G protein beta subunit-like protein
Lst8, s. cerevisiae, homolog of; lst8
Wat1, s. pombe, homolog of; wat1
Pop3, s. pombe, homolog of; pop3

CLONING

Rodgers et al. (2001) cloned rat Gbl and identified its human homolog by database analysis. The predicted human GBL protein shares 96.6% amino acid identity with rat Gbl, which contains 7 WD40 repeats similar to those of G protein beta subunits (see 139380). Northern blot analysis detected ubiquitous expression of Gbl in rat tissues. Immunoprecipitation of membrane and cytosolic fractions of transfected human embryonic kidney cells showed that rat Gbl was predominantly cytosolic.

MAPPING

Rodgers et al. (2001) stated that the GBL gene maps to chromosome 16p13.3.

BIOCHEMICAL FEATURES

- Crystal Structure Yang et al. (2013) reported cocrystal structures of a complex of truncated mTOR (601231) and mammalian lethal with SEC13 protein-8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures revealed an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12 (186945)-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry showed that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. Yang et al. (2013) concluded that the structures also revealed active-site residues and conformational changes that underlie inhibitor potency and specificity.

GENE FUNCTION

Using Western blot and RT-PCR analyses, Rodgers et al. (2001) found that insulin upregulated Gbl protein and mRNA levels in fully differentiated mouse adipocytes in a concentration-dependent manner. MTOR (FRAP1) and raptor (607130) are components of a signaling pathway that regulates cell growth in response to nutrients and growth factors. By immunoprecipitation analysis, Kim et al. (2003) identified GBL as an additional subunit of the MTOR signaling complex in human embryonic kidney cells. GBL bound the kinase domain of MTOR and stabilized the interaction of raptor with MTOR. Loss-of-function experiments using small interfering RNA showed that, like MTOR and raptor, GBL participated in nutrient- and growth factor-mediated signaling to S6K1 (RPS6KB1; 608938), a downstream effector of MTOR, and in control of cell size. Binding of GBL to MTOR strongly stimulated MTOR kinase activity toward S6K1 and 4EBP1 (EIF4EPB1; 602223), and this effect was reversed by stable interaction of raptor with MTOR. Nutrients and rapamycin regulated the association of MTOR with raptor only in complexes that also contained GBL. Kim et al. (2003) proposed that GBL and raptor function together to modulate MTOR kinase activity. ... More on the omim web site

Subscribe to this protein entry history

May 12, 2019: Protein entry updated
Automatic update: model status changed

Nov. 17, 2018: Protein entry updated
Automatic update: model status changed

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Oct. 27, 2017: Protein entry updated
Automatic update: model status changed

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 612190 was added.

Feb. 24, 2016: Protein entry updated
Automatic update: model status changed