Alternative titles; symbols
HGNC Approved Gene Symbol: RANGAP1
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38): 22:41,244,779-41,302,369 (from NCBI)
RAS-related small GTP-binding proteins (GTPBPs), such as RAN (601179), participate in various intracellular signal transduction pathways. The GTP-bound form usually represents the active signaling form of the protein. Hydrolysis of GTP to GDP and phosphate occurs upon activation of a latent GTPase activity in the GTPBP and returns it to its inactive, GDP-bound state. This latent GTPase activity is induced upon interaction of GTP-bound GTPBPs with GTPase-activating proteins (GAPs). Bischoff et al. (1994) purified a GAP from a HeLa cell extract. The protein, designated RanGAP1, is a homodimeric 65-kD polypeptide. RanGAP1 specifically induced the GTPase activity of RAN, but not of RAS (190020), by over 1,000-fold. Bischoff et al. (1994) believed RanGAP1 to be the immediate antagonist of RCC1 (179710), a regulator molecule that keeps RAN in the active, GTP-bound state.
Bischoff et al. (1995) purified the 65-kD RanGAP1 protein from human HeLa cells. Using PCR with degenerate primers based on RanGAP1 peptide sequences, they cloned the corresponding cDNA from a HeLa cell library. The RANGAP1 gene encodes a 587-amino acid polypeptide. The sequence is unrelated to that of GTPase activators for other RAS-related proteins, but is 88% identical to Fug1, the murine homolog of yeast Rna1p. Bischoff et al. (1995) proposed that RanGAP1 and RCC1 control RAN-dependent transport between the nucleus and cytoplasm.
RAN is a nuclear RAS-like GTPase that is required for the bidirectional transport of proteins and ribonucleoproteins across the nuclear pore complex (NPC). RanGAP1 is a key regulator of the RAN GTP/GDP cycle. Matunis et al. (1996) reported the identification and localization of a novel form of RanGAP1. They showed that the 70-kD unmodified form of RanGAP1 is exclusively cytoplasmic, whereas the 90-kD modified form is associated with the cytoplasmic fibers of the NPC. The modified form also appeared to associate with the mitotic spindle apparatus during mitosis. These findings had specific implications for RAN function and broad implications for protein regulation by ubiquitin-like modifications.
RANGAP1 is modified by the conjugation of SUMO1 (601912), and this modification is required for association of RANGAP1 with the nuclear pore complex. Okuma et al. (1999) showed that human SUA1 (SAE1; 613294), UBA2 (613295), and UBC9 (UBE2I; 601661) catalyzed in vitro sumoylation of RANGAP1 in a 2-step reaction.
The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the C9ORF72 gene (614260.0001) is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTDALS1; see 105550). To discover RNA-binding proteins that genetically modify G4C2-mediated neurogenesis, Zhang et al. (2015) performed a candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats. They identified RanGAP (the Drosophila ortholog of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppressed neurodegeneration. RanGAP physically interacted with HRE RNA and was mislocalized in HRE-expressing flies, neurons from C9ORF72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9ORF72 ALS patient brain tissue. Nuclear import was impaired as a result of HRE expression in the fly model and in C9ORF72 iPSC-derived neurons, and these deficits were rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Zhang et al. (2015) suggested that nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
Crystal Structure
Seewald et al. (2002) presented the 3-dimensional structure of a Ran-RanBP1-RanGAP ternary complex in the ground state and in a transition-state mimic. The structure and biochemical experiments showed that RanGAP does not act through an arginine finger, that the basic machinery for fast GTP hydrolysis is provided exclusively by Ran, and that correct positioning of the catalytic glutamine is essential for catalysis.
Bernier-Villamor et al. (2002) performed crystallographic analysis of a complex between mammalian UBC9 and a C-terminal domain of RANGAP1 at 2.5 angstroms. These experiments revealed structural determinants for recognition of consensus SUMO modification sequences found within SUMO-conjugated proteins. Structure-based mutagenesis and biochemical analysis of UBC9 and RANGAP1 revealed distinct motifs required for substrate binding and SUMO modification of p53 (191170), NFKBIA (164008), and RANGAP1.
Reverter and Lima (2005) described the 3.0-angstrom crystal structure of a 4-protein complex of UBC9, a NUP358/RANBP2 (601181) E3 ligase domain (IR1-M), and SUMO1 conjugated to the carboxy-terminal domain of RANGAP1. Structural insights, combined with biochemical and kinetic data obtained with additional substrates, supported a model in which NUP358/RANBP2 acts as an E3 by binding both SUMO and UBC9 to position the SUMO-E2-thioester in an optimal orientation to enhance conjugation.
Bernier-Villamor, V., Sampson, D. A., Matunis, M. J., Lima, C. D. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell 108: 345-356, 2002. [PubMed: 11853669] [Full Text: https://doi.org/10.1016/s0092-8674(02)00630-x]
Bischoff, F. R., Klebe, C., Kretschmer, J., Wittinghofer, A., Ponstingl, H. RanGAP1 induces GTPase activity of nuclear Ras-related Ran. Proc. Nat. Acad. Sci. 91: 2587-2591, 1994. [PubMed: 8146159] [Full Text: https://doi.org/10.1073/pnas.91.7.2587]
Bischoff, F. R., Krebber, H., Kempf, T., Hermes, I., Ponstingl, H. Human RanGTPase-activating protein RanGAP1 is a homologue of yeast Rna1p involved in mRNA processing and transport. Proc. Nat. Acad. Sci. 92: 1749-1753, 1995. [PubMed: 7878053] [Full Text: https://doi.org/10.1073/pnas.92.5.1749]
Matunis, M. J., Coutavas, E., Blobel, G. A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J. Cell Biol. 135: 1457-1470, 1996. [PubMed: 8978815] [Full Text: https://doi.org/10.1083/jcb.135.6.1457]
Okuma, T., Honda, R., Ichikawa, G., Tsumagari, N., Yasuda, H. In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2. Biochem. Biophys. Res. Commun. 254: 693-698, 1999. [PubMed: 9920803] [Full Text: https://doi.org/10.1006/bbrc.1998.9995]
Reverter, D., Lima, C. D. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. (Letter) Nature 435: 687-692, 2005. [PubMed: 15931224] [Full Text: https://doi.org/10.1038/nature03588]
Seewald, M. J., Korner, C., Wittinghofer, A., Vetter, I. R. RanGAP mediates GTP hydrolysis without an arginine finger. Nature 415: 662-666, 2002. [PubMed: 11832950] [Full Text: https://doi.org/10.1038/415662a]
Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., Daley, E. L., Miller, S. J., Cunningham, K. M., Vidensky, S., Gupta, S., Thomas, M. A., and 9 others. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525: 56-61, 2015. [PubMed: 26308891] [Full Text: https://doi.org/10.1038/nature14973]