Emerin Explained

Emerin is a protein that in humans is encoded by the EMD gene, also known as the STA gene. Emerin, together with LEMD3, is a LEM domain-containing integral protein of the inner nuclear membrane in vertebrates. Emerin is highly expressed in cardiac and skeletal muscle. In cardiac muscle, emerin localizes to adherens junctions within intercalated discs where it appears to function in mechanotransduction of cellular strain and in beta-catenin signaling. Mutations in emerin cause X-linked recessive Emery–Dreifuss muscular dystrophy, cardiac conduction abnormalities and dilated cardiomyopathy.

It is named after Alan Emery.^[1]

Structure

Emerin is a 29.0 kDa (34 kDa observed MW) protein composed of 254 amino acids.^[2] Emerin is a serine-rich protein with an N-terminal 20-amino acid hydrophobic region that is flanked by charged residues; the hydrophobic region may be important for anchoring the protein to the membrane, with the charged terminal tails being cytosolic.^[3] In cardiac, skeletal, and smooth muscle, emerin localizes to the inner nuclear membrane;^{[4] [5]} expression of emerin is highest in skeletal and cardiac muscle.^[3] In cardiac muscle specifically, emerin also resides at adherens junctions within intercalated discs.^{[6] [7]}

Function

Emerin is a serine-rich nuclear membrane protein and a member of the nuclear lamina-associated protein family. It mediates membrane anchorage to the cytoskeleton. Emery–Dreifuss muscular dystrophy is an X-linked inherited degenerative myopathy resulting from mutation in the EMD (also known clinically as STA) gene.^[8] Emerin appears to be involved in mechanotransduction, as emerin-deficient mouse fibroblasts failed to transduce normal mechanosensitive gene expression responses to strain stimuli.^[9] In cardiac muscle, emerin is also found complexed to beta-catenin at adherens junctions of intercalated discs, and cardiomyocytes from hearts lacking emerin showed beta-catenin redistribution as well as perturbed intercalated disc architecture and myocyte shape. This interaction appears to be regulated by glycogen synthase kinase 3 beta.^[10]

Clinical significance

Mutations in emerin cause X-linked recessive Emery–Dreifuss muscular dystrophy, which is characterized by early contractures in the Achilles tendons, elbows and post-cervical muscles; muscle weakness proximal in the upper limbs and distal in lower limbs; along with cardiac conduction defects that range from sinus bradycardia, PR prolongation to complete heart block.^[11] In these patients, immunostaining of emerin is lost in various tissues, including muscle, skin fibroblasts, and leukocytes, however diagnostic protocols involve mutational analysis rather than protein staining.^[11] In nearly all cases, mutations result in a complete deletion, or undetectable levels, of emerin protein. Approximately 20% of cases have X chromosomes with an inversion within the Xq28 region.^[12]

Moreover, recent research have found that the absence of functional emerin may decrease the infectivity of HIV-1. Thus, it is speculated that patients with Emery–Dreifuss muscular dystrophy may have immunity to or show an irregular infection pattern to HIV-1.^[13]

Interactions

Emerin has been shown to interact with:

• ACTA1,^[14]
• ACTG2,^[14]
• BANF1,^{[15] [16]}
• BCLAF1,^[17]
• CTNNB1,^{[18] [19]}
• GMCL1,^[16]
• LMNA,^{[14] [20] [21]}
• PSME1,
• SYNE1,^{[22] [23] [24]}
• SYNE2,^{[22] [24] [25]}
• TMEM43,^[26] and
• YTHDC1.^[27]

Further reading

• Gant TM, Wilson KL . Nuclear assembly. . Annu. Rev. Cell Dev. Biol. . 13 . 669–95 . 1998 . 9442884 . 10.1146/annurev.cellbio.13.1.669 .
• Helbling-Leclerc A, Bonne G, Schwartz K . Emery–Dreifuss muscular dystrophy. . Eur. J. Hum. Genet. . 10 . 3 . 157–61 . 2002 . 11973618 . 10.1038/sj.ejhg.5200744 . free .
• Holaska JM, Wilson KL . Multiple roles for emerin: implications for Emery–Dreifuss muscular dystrophy . The Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology . 288 . 7 . 676–80 . 2006 . 16761279 . 2559942 . 10.1002/ar.a.20334 .
• Bione S, Tamanini F, Maestrini E, Tribioli C, Poustka A, Torri G, Rivella S, Toniolo D . Transcriptional organization of a 450-kb region of the human X chromosome in Xq28 . Proc. Natl. Acad. Sci. U.S.A. . 90 . 23 . 10977–81 . 1994 . 8248200 . 47904 . 10.1073/pnas.90.23.10977 . free .
• Bione S, Small K, Aksmanovic VM, D'Urso M, Ciccodicola A, Merlini L, Morandi L, Kress W, Yates JR, Warren ST . Identification of new mutations in the Emery–Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease . Hum. Mol. Genet. . 4 . 10 . 1859–63 . 1996 . 8595407 . 10.1093/hmg/4.10.1859 .
• Yamada T, Kobayashi T . A novel emerin mutation in a Japanese patient with Emery–Dreifuss muscular dystrophy . Hum. Genet. . 97 . 5 . 693–4 . 1996 . 8655156 . 10.1007/BF02281886 . 32857705 .
• Chen EY, Zollo M, Mazzarella R, Ciccodicola A, Chen CN, Zuo L, Heiner C, Burough F, Repetto M, Schlessinger D, D'Urso M . Long-range sequence analysis in Xq28: thirteen known and six candidate genes in 219.4 kb of high GC DNA between the RCP/GCP and G6PD loci . Hum. Mol. Genet. . 5 . 5 . 659–68 . 1997 . 8733135 . 10.1093/hmg/5.5.659 . free .
• Ellis JA, Craxton M, Yates JR, Kendrick-Jones J . Aberrant intracellular targeting and cell cycle-dependent phosphorylation of emerin contribute to the Emery–Dreifuss muscular dystrophy phenotype . J. Cell Sci. . 111 . 6 . 781–92 . 1998 . 10.1242/jcs.111.6.781 . 9472006 .
• Squarzoni S, Sabatelli P, Ognibene A, Toniolo D, Cartegni L, Cobianchi F, Petrini S, Merlini L, Maraldi NM . Immunocytochemical detection of emerin within the nuclear matrix . Neuromuscul. Disord. . 8 . 5 . 338–44 . 1998 . 9673989 . 10.1016/S0960-8966(98)00031-5 . 6113119 .
• Ellis JA, Yates JR, Kendrick-Jones J, Brown CA . Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery–Dreifuss muscular dystrophy . Hum. Genet. . 104 . 3 . 262–8 . 1999 . 10323252 . 10.1007/s004390050946 . 26202307 .
• Squarzoni S, Sabatelli P, Capanni C, Petrini S, Ognibene A, Toniolo D, Cobianchi F, Zauli G, Bassini A, Baracca A, Guarnieri C, Merlini L, Maraldi NM . Emerin presence in platelets . Acta Neuropathol. . 100 . 3 . 291–8 . 2001 . 10965799 . 10.1007/s004019900169 . 6097295 .
• Martins SB, Eide T, Steen RL, Jahnsen T, Skålhegg BS, Collas P . HA95 is a protein of the chromatin and nuclear matrix regulating nuclear envelope dynamics . J. Cell Sci. . 113 . 21 . 3703–13 . 2001 . 10.1242/jcs.113.21.3703 . 11034899 . free .
• Hartley JL, Temple GF, Brasch MA . DNA Cloning Using In Vitro Site-Specific Recombination . Genome Res. . 10 . 11 . 1788–95 . 2001 . 11076863 . 310948 . 10.1101/gr.143000 .
• Laguri C, Gilquin B, Wolff N, Romi-Lebrun R, Courchay K, Callebaut I, Worman HJ, Zinn-Justin S . Structural characterization of the LEM motif common to three human inner nuclear membrane proteins . Structure . 9 . 6 . 503–11 . 2001 . 11435115 . 10.1016/S0969-2126(01)00611-6 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Emery–Dreifuss muscular dystrophy

Notes and References

1. 118-119.
2. Web site: Protein sequence of human EMD (Uniprot ID: P50402). Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 16 September 2015. https://web.archive.org/web/20160304110416/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P50402. 4 March 2016. dead.
3. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D . Identification of a novel X-linked gene responsible for Emery–Dreifuss muscular dystrophy . Nature Genetics . 8 . 4 . 323–7 . Dec 1994 . 7894480 . 10.1038/ng1294-323 . 7719215 .
4. Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J, Okada R, Hayashi YK, Tsukahara T, Arahata K . Emerin deficiency at the nuclear membrane in patients with Emery–Dreifuss muscular dystrophy . Nature Genetics . 12 . 3 . 254–9 . Mar 1996 . 8589715 . 10.1038/ng0396-254 . 11030787 .
5. Manilal S, Nguyen TM, Sewry CA, Morris GE . The Emery–Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein . Human Molecular Genetics . 5 . 6 . 801–8 . Jun 1996 . 8776595 . 10.1093/hmg/5.6.801. free .
6. Cartegni L, di Barletta MR, Barresi R, Squarzoni S, Sabatelli P, Maraldi N, Mora M, Di Blasi C, Cornelio F, Merlini L, Villa A, Cobianchi F, Toniolo D . Heart-specific localization of emerin: new insights into Emery–Dreifuss muscular dystrophy . Human Molecular Genetics . 6 . 13 . 2257–64 . Dec 1997 . 9361031 . 10.1093/hmg/6.13.2257. free .
7. Manilal S, Sewry CA, Pereboev A, Man N, Gobbi P, Hawkes S, Love DR, Morris GE . Distribution of emerin and lamins in the heart and implications for Emery–Dreifuss muscular dystrophy . Human Molecular Genetics . 8 . 2 . 353–9 . Feb 1999 . 9949197 . 10.1093/hmg/8.2.353. free .
8. Web site: Entrez Gene: EMD emerin (Emery–Dreifuss muscular dystrophy).
9. Lammerding. J. Hsiao. J. Schulze. PC. Kozlov. S. Stewart. CL. Lee. RT. Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells.. The Journal of Cell Biology. 29 August 2005. 170. 5. 781–91. 16115958. 10.1083/jcb.200502148. 2171355.
10. Wheeler. MA. Warley. A. Roberts. RG. Ehler. E. Ellis. JA. Identification of an emerin-beta-catenin complex in the heart important for intercalated disc architecture and beta-catenin localisation.. Cellular and Molecular Life Sciences. March 2010. 67. 5. 781–96. 19997769. 10.1007/s00018-009-0219-8. 27205170. 11115513.
11. Emery AE . Emery–Dreifuss muscular dystrophy - a 40 year retrospective . Neuromuscular Disorders . 10 . 4–5 . 228–32 . Jun 2000 . 10838246 . 10.1016/s0960-8966(00)00105-x. 26523560 .
12. Small K, Warren ST . Emerin deletions occurring on both Xq28 inversion backgrounds . Human Molecular Genetics . 7 . 1 . 135–9 . Jan 1998 . 9384614 . 10.1093/hmg/7.1.135. free .
13. Li M, Craigie R . Virology: HIV goes nuclear . Nature . 441 . 7093 . 581–2 . Jun 2006 . 16738646 . 10.1038/441581a . 2006Natur.441..581L . free .
14. Lattanzi G, Cenni V, Marmiroli S, Capanni C, Mattioli E, Merlini L, Squarzoni S, Maraldi NM . Association of emerin with nuclear and cytoplasmic actin is regulated in differentiating myoblasts . Biochemical and Biophysical Research Communications . 303 . 3 . 764–70 . Apr 2003 . 12670476 . 10.1016/s0006-291x(03)00415-7 .
15. Berk JM, Simon DN, Jenkins-Houk CR, Westerbeck JW, Grønning-Wang LM, Carlson CR, Wilson KL . The molecular basis of emerin-emerin and emerin-BAF interactions . Journal of Cell Science . 127 . Pt 18 . 3956–69 . Sep 2014 . 25052089 . 10.1242/jcs.148247 . 4163644.
16. Holaska JM, Lee KK, Kowalski AK, Wilson KL . Transcriptional repressor germ cell-less (GCL) and barrier to autointegration factor (BAF) compete for binding to emerin in vitro . The Journal of Biological Chemistry . 278 . 9 . 6969–75 . Feb 2003 . 12493765 . 10.1074/jbc.M208811200 . free .
17. Haraguchi T, Holaska JM, Yamane M, Koujin T, Hashiguchi N, Mori C, Wilson KL, Hiraoka Y . Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery–Dreifuss muscular dystrophy . European Journal of Biochemistry . 271 . 5 . 1035–45 . Mar 2004 . 15009215 . 10.1111/j.1432-1033.2004.04007.x.
18. Wheeler MA, Warley A, Roberts RG, Ehler E, Ellis JA . Identification of an emerin-beta-catenin complex in the heart important for intercalated disc architecture and beta-catenin localisation . Cellular and Molecular Life Sciences . 67 . 5 . 781–96 . Mar 2010 . 19997769 . 10.1007/s00018-009-0219-8 . 27205170 . 11115513 .
19. Markiewicz E, Tilgner K, Barker N, van de Wetering M, Clevers H, Dorobek M, Hausmanowa-Petrusewicz I, Ramaekers FC, Broers JL, Blankesteijn WM, Salpingidou G, Wilson RG, Ellis JA, Hutchison CJ . The inner nuclear membrane protein emerin regulates beta-catenin activity by restricting its accumulation in the nucleus . The EMBO Journal . 25 . 14 . 3275–85 . Jul 2006 . 16858403 . 10.1038/sj.emboj.7601230 . 1523183.
20. Sakaki M, Koike H, Takahashi N, Sasagawa N, Tomioka S, Arahata K, Ishiura S . Interaction between emerin and nuclear lamins . Journal of Biochemistry . 129 . 2 . 321–7 . Feb 2001 . 11173535 . 10.1093/oxfordjournals.jbchem.a002860 .
21. Clements L, Manilal S, Love DR, Morris GE . Direct interaction between emerin and lamin A . Biochemical and Biophysical Research Communications . 267 . 3 . 709–14 . Jan 2000 . 10673356 . 10.1006/bbrc.1999.2023 .
22. Zhang Q, Skepper JN, Yang F, Davies JD, Hegyi L, Roberts RG, Weissberg PL, Ellis JA, Shanahan CM . Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues . Journal of Cell Science . 114 . Pt 24 . 4485–98 . Dec 2001 . 10.1242/jcs.114.24.4485 . 11792814 .
23. Mislow JM, Holaska JM, Kim MS, Lee KK, Segura-Totten M, Wilson KL, McNally EM . Nesprin-1alpha self-associates and binds directly to emerin and lamin A in vitro . FEBS Letters . 525 . 1–3 . 135–40 . Aug 2002 . 12163176 . 10.1016/s0014-5793(02)03105-8. free .
24. Wheeler MA, Davies JD, Zhang Q, Emerson LJ, Hunt J, Shanahan CM, Ellis JA . 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 . Experimental Cell Research . 313 . 13 . 2845–57 . Aug 2007 . 17462627 . 10.1016/j.yexcr.2007.03.025 .
25. Zhang Q, Ragnauth CD, Skepper JN, Worth NF, Warren DT, Roberts RG, Weissberg PL, Ellis JA, Shanahan CM . Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle . Journal of Cell Science . 118 . Pt 4 . 673–87 . Feb 2005 . 15671068 . 10.1242/jcs.01642 . free .
26. Bengtsson L, Otto H . LUMA interacts with emerin and influences its distribution at the inner nuclear membrane . Journal of Cell Science . 121 . Pt 4 . 536–48 . Feb 2008 . 18230648 . 10.1242/jcs.019281 . free .
27. Wilkinson FL, Holaska JM, Zhang Z, Sharma A, Manilal S, Holt I, Stamm S, Wilson KL, Morris GE . Emerin interacts in vitro with the splicing-associated factor, YT521-B . European Journal of Biochemistry . 270 . 11 . 2459–66 . Jun 2003 . 12755701 . 10.1046/j.1432-1033.2003.03617.x . free .