SYNE2 explained

Nesprin-2 is a protein that in humans is encoded by the SYNE2 gene.^{[1] [2] [3]} The human SYNE2 gene consists of 116 exons and encodes nesprin-2, a member of the nuclear envelope (NE) spectrin-repeat (nesprin) family. Nesprins are modular proteins with a central extended spectrin-repeat (SR) rod domain and a C-terminal Klarsicht/ANC-1/Syne homology (KASH) transmembrane domain, which acts as a NE-targeting motif. Nesprin-2 (Nesp2) binds to cytoplasmic F-actin, tethering the nucleus to the cytoskeleton and maintaining the structural integrity of the nucleus.

The human SYNE2 gene encodes a protein of 6,885 amino acids (isoform 1, Nesp2 giant); alternative mRNA splicing produces transcripts encoding a larger isoform and numerous smaller isoforms, some of which are specific to various tissues; alternative start and termination sites within the mRNA also allow translation of smaller isoforms, many possessing unique N- or C-terminal sequences encoded by retained introns. Two mechanisms create splice variants of nesprin-2 with the KASH domain deleted (deltaKASH). In deltaKASH1 variants, deletion of cassette exons 111-112 results in a frame shift that disrupts the KASH domain but retains the 3' untranslated region (UTR) in exon 116 utilized for isoforms containing the KASH domain. This mechanism, which also occurs in SYNE1 mRNA encoding nesprin-1 (enaptin), generates deltaKASH1 isoforms terminating with a distinct 11-amino acid tail (GIAGHSATPPA replacing YPMLRYTNGPPPT in isoforms with KASH). Utilization of an alternative stop codon in exon 115, which is followed by a distinct 3' UTR, generates deltaKASH2 variants. This mechanism truncates larger isoforms without generating a distinct C-terminal sequence. Expression of deltaKASH1 variants occurs largely in brain and kidney, with smaller amounts in heart; deltaKASH2 variants are detected in heart and spleen.^[4]

Further reading

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• Zhang Q, Skepper JN, Yang F, etal . Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues. . J. Cell Sci. . 114 . Pt 24 . 4485–98 . 2002 . 10.1242/jcs.114.24.4485 . 11792814 .
• Zhen YY, Libotte T, Munck M, etal . NUANCE, a giant protein connecting the nucleus and actin cytoskeleton. . J. Cell Sci. . 115 . Pt 15 . 3207–22 . 2003 . 10.1242/jcs.115.15.3207 . 12118075 .
• Zhang Q, Ragnauth C, Greener MJ, etal . The nesprins are giant actin-binding proteins, orthologous to Drosophila melanogaster muscle protein MSP-300. . Genomics . 80 . 5 . 473–81 . 2003 . 12408964 . 10.1016/S0888-7543(02)96859-X .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Heilig R, Eckenberg R, Petit JL, etal . The DNA sequence and analysis of human chromosome 14. . Nature . 421 . 6923 . 601–7 . 2003 . 12508121 . 10.1038/nature01348 . 2003Natur.421..601H . free .
• Schirmer EC, Florens L, Guan T, etal . Nuclear membrane proteins with potential disease links found by subtractive proteomics. . Science . 301 . 5638 . 1380–2 . 2003 . 12958361 . 10.1126/science.1088176 . 2003Sci...301.1380S . 23832536 .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs. . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Zhang Q, Ragnauth CD, Skepper JN, etal . Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle. . J. Cell Sci. . 118 . Pt 4 . 673–87 . 2005 . 15671068 . 10.1242/jcs.01642 . free .
• Cheng J, Kapranov P, Drenkow J, etal . Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. . Science . 308 . 5725 . 1149–54 . 2005 . 15790807 . 10.1126/science.1108625 . 2005Sci...308.1149C . 13047538 .
• Libotte T, Zaim H, Abraham S, etal . Lamin A/C-dependent localization of Nesprin-2, a giant scaffolder at the nuclear envelope. . Mol. Biol. Cell . 16 . 7 . 3411–24 . 2005 . 15843432 . 10.1091/mbc.E04-11-1009 . 1165422 .
• Padmakumar VC, Libotte T, Lu W, etal . The inner nuclear membrane protein Sun1 mediates the anchorage of Nesprin-2 to the nuclear envelope. . J. Cell Sci. . 118 . Pt 15 . 3419–30 . 2005 . 16079285 . 10.1242/jcs.02471 . free .
• Kimura K, Wakamatsu A, Suzuki Y, etal . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 10.1101/gr.4039406 . 1356129 .
• Olsen JV, Blagoev B, Gnad F, etal . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. . Cell . 127 . 3 . 635–48 . 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . free .
• Wheeler MA, Davies JD, Zhang Q, etal . Distinct functional domains in nesprin-1alpha and nesprin-2beta bind directly to emerin and both interactions are disrupted in X-linked Emery–Dreifuss muscular dystrophy. . Exp. Cell Res. . 313 . 13 . 2845–57 . 2007 . 17462627 . 10.1016/j.yexcr.2007.03.025 .

Notes and References

1. Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Res . 6 . 1 . 63–70 . Jul 1999 . 10231032 . 10.1093/dnares/6.1.63 . free .
2. Apel ED, Lewis RM, Grady RM, Sanes JR . Syne-1, a dystrophin- and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction . J Biol Chem . 275 . 41 . 31986–95 . Nov 2000 . 10878022 . 10.1074/jbc.M004775200 . free .
3. Web site: Entrez Gene: SYNE2 spectrin repeat containing, nuclear envelope 2.
4. Rajgor D, Mellad JA, Autore F, Zhang Q, Shanahan CM . Multiple novel nesprin-1 and nesprin-2 variants act as versatile tissue-specific intracellular scaffolds . PLOS ONE . 7 . 7 . e40098 . Jul 2012 . 22768332 . 3388047. 10.1371/journal.pone.0040098 . 2012PLoSO...740098R . free .