MTOR (FRAP1; 601231), the target of the immunosuppressive drug rapamycin, is the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth. Kim et al. (2002) reported that MTOR forms a stoichiometric complex with RAPTOR, an evolutionarily conserved protein with at least 2 roles in the MTOR pathway. They cloned the full-length cDNA for RAPTOR, which contains an open reading frame encoding a protein with 1,335 amino acids and a predicted molecular mass of 149 kD. A previously identified partial cDNA, KIAA1303 (Nagase et al., 2000), is contained within the RAPTOR cDNA. All RAPTOR homologs have a novel N-terminal domain the authors called RNC (RAPTOR N-terminal conserved) that consists of 3 blocks with at least 67 to 79% sequence similarity and is predicted to have a high propensity to form alpha helices. Following the RNC domain, all RAPTOR homologs have 3 HEAT repeats, which are followed by 7 WD40 repeats in the C-terminal third of the protein. Northern blot analysis showed that RAPTOR is expressed in all tissues in a pattern similar to that of MTOR, with the highest levels of both mRNAs in skeletal muscle, brain, kidney, and placenta.

Independently, Hara et al. (2002) also cloned the RAPTOR gene. They found that RAPTOR is a 150-kD MTOR-binding protein that also binds eukaryotic initiation factor 4E-binding protein-1 (4EBP1; 602223) and p70 S6 kinase-alpha (S6K1; 608938). They determined that mouse and human RAPTOR share about 97% amino acid identity.

Kim et al. (2002) showed that RAPTOR has a positive role in nutrient-stimulated signaling to the downstream effector S6K1, maintenance of cell size, and MTOR protein expression. The association of RAPTOR with MTOR also negatively regulates the MTOR kinase activity. Conditions that repress the pathway, such as nutrient deprivation and mitochondrial uncoupling, stabilize the MTOR-RAPTOR association and inhibit MTOR kinase activity. The authors proposed that RAPTOR is a component of the MTOR pathway that, through its association with MTOR, regulates cell size in response to nutrient levels.

Hara et al. (2002) showed that the binding of RAPTOR to MTOR is necessary for the MTOR-catalyzed phosphorylation of 4EBP1 in vitro and that it strongly enhances the MTOR kinase activity toward p70-alpha. Rapamycin or amino acid withdrawal increased, whereas insulin strongly inhibited, the recovery of 4EBP1 and RAPTOR on 7-methyl-GTP sepharose. Partial inhibition of RAPTOR expression by RNA interference reduced MTOR-catalyzed 4EBP1 phosphorylation in vitro. RNA interference of C. elegans Raptor yielded an array of phenotypes that closely resembled those produced by inactivation of CE-Tor. Thus, the authors concluded that RAPTOR is an essential scaffold for the MTOR-catalyzed phosphorylation of 4EBP1 and mediates TOR action in vivo.

By immunoprecipitation analysis, Kim et al. (2003) identified GBL (612190) 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 and in control of cell size. Binding of GBL to MTOR strongly stimulated MTOR kinase activity toward S6K1 and 4EBP1, 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.

The multiprotein mTORC1 protein kinase complex (see 601231) is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. Sancak et al. (2008) found that the Rag proteins, a family of 4 related small guanosine triphosphatases (GTPases) (RAGA (612194), RAGB (300725), RAGC (608267), and RAGD (608268)) interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. Coimmunoprecipitation assays indicated that RAPTOR is the key mediator of the Rag-mTORC1 interaction.

Meade et al. (2018) found that the poxvirus F17 protein bound to the RNC domain in Raptor in a manner dependent on phosphorylation of ser53 and ser62 in F17. Binding of F17 to Raptor competed with binding of MTOR to Raptor in host cells, thereby dysregulating MTOR-mediated host antiviral responses.

Cryoelectron Microscopy

Aylett et al. (2016) resolved the architecture of the human mTORC1 complex, containing mTOR with subunits Raptor and mLST8 (612190), bound to FK506-binding protein (FKBP; 186945)-rapamycin, by combining cryoelectron microscopy at 5.9-angstrom resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3-angstrom resolution. The structure explained how FKBP-rapamycin and architectural elements of mTORC1 limit access to the recessed active site. Consistent with a role in substrate recognition and delivery, the conserved amino-terminal domain of Raptor is juxtaposed to the kinase active site.

By genomic sequence analysis, Kim et al. (2002) mapped the RPTOR gene to chromosome 17q25.3.

In a dataset of 233 parent-offspring trios with psoriasis (see 177900), Capon et al. (2004) analyzed 8 representative SNPs selected from 2 psoriasis susceptibility (PSORS2; 602723) association peaks previously identified by Helms et al. (2003) encompassing the SLC9AR1 (604990)-NAT9 (620913) genes and the third intron of the RAPTOR gene, respectively. They found evidence for association only at RAPTOR rs2019154 (p = 0.027). Restricting the analysis to 116 trios with a well-documented family history of psoriasis increased the significance of the association for 3 RAPTOR SNPs, with rs2019154 yielding a p value of 0.008.

In a study of 579 pedigrees with psoriasis, Stuart et al. (2006) found no evidence for a disease association with 3 SNPS in the RAPTOR gene.