Alternative titles; symbols
HGNC Approved Gene Symbol: SEC13
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:10,300,931-10,321,112 (from NCBI)
Bidirectional transport of macromolecules between the cytoplasm and nucleus occurs through nuclear pore complexes (NPCs) embedded in the nuclear envelope. NPCs are composed of subcomplexes, and SEC13L1 is part of one such subcomplex, NUP107 (607617)-NUP160 (607614) (Loiodice et al., 2004).
Gieser and Swaroop (1992) described sequence tagged sites (STSs) from 58 novel directionally cloned human cDNAs from an enriched retinal pigment epithelial cell line library. The nucleotide sequence of one of the cDNA clones, AA35 (D3S1231E), showed strong homology to the yeast SEC13 gene, which is required for vesicle biogenesis from endoplasmic reticulum during the transport of proteins. Swaroop et al. (1994) designated the human gene SEC13R. The predicted amino acid sequence of the SEC13R gene product shows 70% similarity to the yeast protein. The deduced polypeptide sequence contains several beta-transducin-like WD40 repeats and is rich in serine and threonine residues. A 1.4-kb transcript of SEC13R was detected by Northern analysis of many human tissues. However, RT-PCR analysis using 2 primer sets from different regions of the gene suggested differential expression of alternatively spliced transcripts in various tissues.
Using the N-terminal region of NUP96 (601021) as bait in a yeast 2-hybrid screen of B-cell, breast, and placenta cDNA libraries, Enninga et al. (2003) cloned SEC13L1, which they called SEC13. The full-length protein contains 322 amino acids. Western blot analysis detected endogenous SEC13L1 at an apparent molecular mass of about 36 kD. Immunoelectron microscopy detected SEC13L1 and NUP96 on both the cytoplasmic and nucleoplasmic sides of the NPC, in addition to other intracellular sites.
By proteomic analysis and mass spectrometry, Cronshaw et al. (2002) identified 94 proteins associated with NPCs purified from rat liver nuclei. Sec13r was relatively abundant, with 16 to 32 copies per NPC.
By mutation analysis, Enninga et al. (2003) determined that the SEC13L1-NUP96 interaction required the WD repeat region of SEC13L1 and residues 201 to 378 of NUP96. SEC13L1 did not bind NUP98 (601021). In mitosis, SEC13L1 was dispersed throughout the cell, whereas a pool of NUP96 colocalized with the spindle apparatus. Photobleaching experiments showed that SEC13L1 shuttled between intranuclear sites and the cytoplasm, and a fraction of SEC13L1 stably associated with NPCs. Cotransfection of SEC13L1 and the SEC13L1-binding site of NUP96 decreased the mobile pool of SEC13L1. Targeting and mutation studies showed that SEC13L1 is actively transported into the nucleus and contains a C-terminal nuclear localization signal.
Loiodice et al. (2004) transfected HeLa cells with cDNAs encoding the constituents of the Nup107-160 subcomplex. All proteins were properly targeted at the nuclear envelope after 2 or 3 days, except for SEC13, which gave an additional signal typical for endoplasmic reticulum (ER) and ER exit sites. Coimmunoprecipitation of SEC13 with NUP37 (609264) confirmed that SEC13 interacts with Nup107-160. The fraction of SEC13 associated with Nup107-160 was targeted to kinetochores from prophase to anaphase during mitosis.
Zuccolo et al. (2007) stated that the NUP107-NUP160 nucleoporin subcomplex contains NUP133 (607613), NUP96, NUP85 (170285), NUP43 (608141), NUP37, SEC13, and SEH1 (SEH1L; 609263). The NUP107-NUP160 subcomplex stably associates on both faces of nuclear pore complexes during interphase, and the entire subcomplex is recruited to chromatin during mitosis. A fraction of the subcomplex localizes at kinetochores during prophase, even before nuclear envelope breakdown. Zuccolo et al. (2007) found that recruitment of the NUP107-NUP160 complex to kinetochores depended mainly on the NDC80 complex (see 607272) and CENPF (600236). The SEH1 subunit of the NUP107-NUP160 complex was essential for targeting the complex to kinetochores. Codepletion of several NUP107-NUP160 subunits or of SEH1 alone resulted in kinetochores that failed to establish proper microtubule attachment, thus inducing a checkpoint-dependent mitotic delay. The mitotic Ran-GTP effector, CRM1 (XPO1; 602559), as well as its binding partner, the RANGAP1 (602362)-RANBP2 (601181) complex, were mislocalized upon depletion of NUP107-NUP160 complex from kinetochores.
Bar-Peled et al. (2013) identified the octameric GATOR (GTPase-activating protein (GAP) activity toward RAGs) complex as a critical regulator of the pathway that signals amino acid sufficiency to mTORC1 (see 601231). GATOR is composed of 2 subcomplexes, GATOR1 and GATOR2. Inhibition of the GATOR1 subunits DEPDC5 (614191), NPRL2 (607072), and NPRL3 (600928) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of the GATOR2 subunits MIOS (615359), WDR24 (620307), WDR59 (617418), SEH1L, and SEC13 suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GAP activity for RAGA (612194) and RAGB (300725), and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, Bar-Peled et al. (2013) concluded that they had identified a key negative regulator of the RAG GTPases and revealed that, like other mTORC1 regulators, RAG function can be deregulated in cancer.
Using cryoelectron microscopy, Valenstein et al. (2022) determined the structure of the human GATOR2 complex at an overall resolution of 3.7 angstroms. GATOR2 adopted a 2-fold rotationally symmetric, cage-like architecture built from 2 WDR24-SEH1L, 4 MIOS-SEH1L, and 2 WDR59-SEC13 heterodimers that assembled together to form an octagonal scaffold with protruding pairs of WD40 beta propellers. The core subunits, WDR24, MIOS, and WDR59, each have a C-terminal domain (CTD) composed of a zinc finger and a RING domain, and they shared a similar fold. Consistent with their key roles in GATOR2 assembly, WDR24, MIOS, and WDR59 were each required for mTORC1 to sense amino acid availability. The 6-bladed beta-propeller proteins SEH1L and SEC13 were incorporated into the GATOR2 scaffold through a beta-blade donation by WDR24 or MIOS and WDR59, respectively. The surface of GATOR2 was highly charged with interspersed lipophilic patches. GATOR2 contained a total of 8 beta-propeller pairs, including 4 central pairs composed of MIOS and SEH1L beta-propeller dimers. MIOS interacted with WDR24 and WDR59 to form heterodimers through their CTDs: 2 between the C termini of MIOS and WDR24, and 2 between the CTDs of MIOS and WDR59, thereby linking 4 MIOS to 2 WDR24 and 2 WDR59. Despite the presence of multiple RING domains, the GATOR2 structure suggested that it does not possess E3 ubiquitin ligase activity, which was confirmed by subsequent biochemical analysis. The alpha-solenoid junctions of SEH1L and SEC13 circularized the GATOR2 complex to complete the scaffold. The GATOR2 complex used beta propellers to engage with amino acid sensors and GATOR1 to regulate mTORC1. Specifically, the MIOS and WDR24 beta propellers received inputs from cytosolic amino acid sensors, and the WDR24 and WDR59 propellers transduced amino acid availability to mTORC1.
By a combination of study of somatic cell hybrids and isotopic in situ hybridization, Swaroop et al. (1994) mapped the SEC13R gene to chromosome 3p25-p24. They physically mapped SEC13R to a YAC clone containing the von Hippel-Lindau disease locus (VHL; 608537). From the diagram they provided, it appeared that SEC13R lies approximately 500 kb centromeric to PMCA2 (108733) and 1,200 kb centromeric to VHL. In the mouse, Swaroop et al. (1994) mapped the Sec13r gene to chromosome 6.
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340: 1100-1106, 2013. [PubMed: 23723238] [Full Text: https://doi.org/10.1126/science.1232044]
Cronshaw, J. M., Krutchinsky, A. N., Zhang, W., Chait, B. T., Matunis, M. J. Proteomic analysis of the mammalian nuclear pore complex. J. Cell Biol. 158: 915-927, 2002. [PubMed: 12196509] [Full Text: https://doi.org/10.1083/jcb.200206106]
Enninga, J., Levay, A., Fontoura, B. M. A. Sec13 shuttles between the nucleus and the cytoplasm and stably interacts with Nup96 at the nuclear pore complex. Molec. Cell. Biol. 23: 7271-7284, 2003. [PubMed: 14517296] [Full Text: https://doi.org/10.1128/MCB.23.20.7271-7284.2003]
Gieser, L., Swaroop, A. Expressed sequence tags and chromosomal localization of cDNA clones from a subtracted retinal pigment epithelium library. Genomics 13: 873-876, 1992. [PubMed: 1639417] [Full Text: https://doi.org/10.1016/0888-7543(92)90173-p]
Loiodice, I., Alves, A., Rabut, G., van Overbeek, M., Ellenberg, J., Sibarita, J.-B., Doye, V. The entire Nup107-160 complex, including three new members, is targeted as one entity to kinetochores in mitosis. Molec. Biol. Cell 15: 3333-3344, 2004. [PubMed: 15146057] [Full Text: https://doi.org/10.1091/mbc.e03-12-0878]
Swaroop, A., Yang-Feng, T. L., Liu, W., Gieser, L., Barrow, L. L., Chen, K.-C., Agarwal, N., Meisler, M. H., Smith, D. I. Molecular characterization of a novel human gene, SEC13R, related to the yeast secretory pathway gene SEC13, and mapping to a conserved linkage group on human chromosome 3p24-p25 and mouse chromosome 6. Hum. Molec. Genet. 3: 1281-1286, 1994. [PubMed: 7987303] [Full Text: https://doi.org/10.1093/hmg/3.8.1281]
Valenstein, M. L., Rogala, K. B., Lalgudi, P. V., Brignole, E. J., Gu, X., Saxton, R. A., Chantranupong, L., Kolibius, J., Quast, J.-P., Sabatini, D. M. Structure of the nutrient-sensing hub GATOR2. Nature 607: 610-616, 2022. [PubMed: 35831510] [Full Text: https://doi.org/10.1038/s41586-022-04939-z]
Zuccolo, M., Alves, A., Galy, V., Bolhy, S., Formstecher, E., Racine, V., Sibarita, J.-B., Fukagawa, T., Shiekhattar, R., Yen, T., Doye, V. The human Nup107-160 nuclear pore subcomplex contributes to proper kinetochore functions. EMBO J. 26: 1853-1864, 2007. [PubMed: 17363900] [Full Text: https://doi.org/10.1038/sj.emboj.7601642]