Alternative titles; symbols
HGNC Approved Gene Symbol: MYCBP2
Cytogenetic location: 13q22.3 Genomic coordinates (GRCh38) : 13:77,044,657-77,327,094 (from NCBI)
Using the transcription-activating domain of MYC (190080) as bait in a yeast 2-hybrid screen of a Burkitt lymphoma cell line cDNA library, followed by screening several cDNA libraries, Guo et al. (1998) obtained a full-length cDNA encoding MYCBP2, which they called PAM. The deduced 4,641-amino acid protein has a calculated molecular mass of 510 kD. PAM contains an N-terminal leucine zipper; 2 RCC1 (179710) homology domains (RHD1 and RHD2) separated by a basic region; a cell division sequence motif; 2 direct repeats of 91 amino acids (PAM repeats); a second leucine zipper; a serine-rich region that contains a domain homologous to histone-binding proteins, such as Xenopus N1/N2 (NASP; 603185); a putative nuclear localization signal; a potential ring zinc finger domain; and 2 putative C2H2-type zinc finger motifs. Northern blot analysis detected highest expression of a 15-kb PAM transcript in brain and thymus. Expression was moderate in skeletal muscle, pancreas, and ovary and weak in all other tissues examined.
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned MYCBP2, which they designated KIAA0916. RT-PCR ELISA detected high expression in brain, low expression in spleen, skeletal muscle, and fetal liver, and moderate expression in all other peripheral tissues and specific brain regions examined.
Using tuberin (TSC; 191092) as bait in a yeast 2-hybrid screen of a human fetal frontal cortex library, Murthy et al. (2004) cloned PAM. Immunofluorescence analysis of cultured primary rat cortical neurons detected strong nuclear Pam staining and punctate staining along axons and dendrites.
By screening a genomic YAC library and sequence analysis, Guo et al. (1998) mapped the MYCBP2 gene to chromosome 13q22.
Guo et al. (1998) determined that a central region of PAM, between the second leucine zipper and the histone-binding protein homology domain, contains the MYC-binding domain.
By coimmunoprecipitation analysis of a rat adrenal pheochromocytoma cell line and rat embryonic brain, Murthy et al. (2004) found that Pam interacted with tuberin in vitro and in vivo.
Pierre et al. (2004) found that PAM localized to the endoplasmic reticulum in HeLa cells. Upon serum stimulation, PAM was recruited by sphingosine-1-phosphate (S1P) to the plasma membrane, where it inhibited adenylyl cyclase (see ADCY1; 103072) activity. S1P inhibited adenylyl cyclase in 2 phases: an initial phase (1 to 10 min), which was PAM independent, and a late phase (20 to 240 min), which was PAM dependent. PAM activation by S1P required protein kinase C (see PRKCA; 176960) and phospholipase C (see PLCB1; 607120) activity.
Gao and Patel (2005) showed that RHD2 of PAM was sufficient for inhibition of Gs-alpha (GNAS; 139320)-stimulated adenylyl cyclase-5 (ADCY5; 600293) activity and that binding of RHD2 to the C2 domain of ADCY5 was necessary, but not sufficient, for this inhibition. Moreover, they identified his912 and his913 of PAM as critical for inhibition of ADCY5.
Pao et al. (2018) performed activity-based protein profiling of homologous to E6-AP carboxy terminus (HECT) or RING-between-RING (RBR)-like E3 ligases and identified the neuron-associated E3 ligase MYCBP2 as the apparent single member of a class of RING-linked E3 ligase with esterification activity and intrinsic selectivity for threonine over serine. MYCBP2 contains 2 essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates. Crystallographic characterization of this class of E3 ligase, which the authors designate RING-Cys-relay (RCR), provided insights into its mechanism and threonine selectivity. Pao et al. (2018) concluded that their findings implicated nonlysine ubiquitination in cellular regulation of higher eukaryotes and suggested that E3 enzymes have an unappreciated mechanistic diversity.
For discussion of a possible association between variation in the MYCBP2 gene and a form of high myopia, see 610392.0001.
This variant is classified as a variant of unknown significance because its contribution to a form of high myopia has not been confirmed.
In a father and 2 daughters with a 'unique' excavated disc anomaly and high myopia due to increased axial lengths, Bredrup et al. (2015) identified heterozygosity for a 5-bp deletion (c.5906_5910del, NM_015057.4) in exon 40 of the MYCBP2 gene, causing a frameshift predicted to result in a premature termination codon (Glu1969ValfsTer26). The mutation, which arose de novo in the father, was not found in an in-house database of 300 Norwegian exomes or in the 1000 Genomes Project or dbSNP databases. The authors noted that exon 40 does not encode a functionally conserved domain of MYCBP2, and that the functional consequence of the 5-bp deletion was unknown. The affected family members exhibited grossly dysplastic optic discs that were deeply excavated on optical coherence tomography. They also had reduced visual acuities with a general reduction of sensitivity on visual field examination, and visual evoked responses showed prolonged latencies. Affected eyes appeared ovoid on MRI, and the father had thin optic nerves. The authors designated the phenotype 'high myopia-excavated disc anomaly.'
Bredrup, C., Johansson, S., Bindoff, L. A., Sztromwasser, P., Krakenes, J., Mellgren, A. E. C., Bruras, K. R., Lind, O., Boman, H., Knappskog, P. M., Rodahl, E. High myopia-excavated optic disc anomaly associated with a frameshift mutation in the MYC-binding protein 2 gene (MYCBP2). Am. J. Ophthal. 159: 973-979, 2015. [PubMed: 25634536] [Full Text: https://doi.org/10.1016/j.ajo.2015.01.021]
Gao, X., Patel, T. B. Histidine residues 912 and 913 in protein associated with Myc are necessary for the inhibition of adenylyl cyclase activity. Molec. Pharm. 67: 42-49, 2005. [PubMed: 15470080] [Full Text: https://doi.org/10.1124/mol.104.005355]
Guo, Q., Xie, J., Dang, C. V., Liu, E. T., Bishop, J. M. Identification of a large Myc-binding protein that contains RCC1-like repeats. Proc. Nat. Acad. Sci. 95: 9172-9177, 1998. [PubMed: 9689053] [Full Text: https://doi.org/10.1073/pnas.95.16.9172]
Murthy, V., Han, S., Beauchamp, R. L., Smith, N., Haddad, L. A., Ito, N., Ramesh, V. Pam and its ortholog highwire interact with and may negatively regulate the TSC1-TSC2 complex. J. Biol. Chem. 279: 1351-1358, 2004. [PubMed: 14559897] [Full Text: https://doi.org/10.1074/jbc.M310208200]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Oharo, O. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 355-364, 1998. [PubMed: 10048485] [Full Text: https://doi.org/10.1093/dnares/5.6.355]
Pao, K.-C., Wood, N. T., Knebel, A., Rafie, K., Stanley, M., Mabbitt, P. D., Sundaramoorthy, R., Hofmann, K., van Aalten, D. M. F., Virdee, S. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature 556: 381-385, 2018. [PubMed: 29643511] [Full Text: https://doi.org/10.1038/s41586-018-0026-1]
Pierre, S. C., Hausler, J., Birod, K., Geisslinger, G., Scholich, K. PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate. EMBO J. 23: 3031-3040, 2004. [PubMed: 15257286] [Full Text: https://doi.org/10.1038/sj.emboj.7600321]