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SUN-Domain Proteins 4572–4573 (2006) PERSPECTIVES 51. Rudd, P. M. & Dwek, R. A. Glycosylation: heterogeneity 63. Wang, L., Xie, J., Deniz, A. A. & Schultz, P. G. Unnatural protein complexes support a broad range of and the 3D structure of proteins. Crit. Rev. Biochem. amino acid mutagenesis of green fluorescent protein. 4 Mol. Biol. 32, 1–100 (1997). J. Org. Chem. 68, 174–176 (2003). functions (BOX 1). At least 80 unique integral 52. Zhang, Z. et al. A new strategy for the synthesis of 64. Wang, L., Brock, A. & Schultz, P. G. Adding L-3-(2- membrane proteins were found to localize glycoproteins. Science 303, 371–373 (2004). naphthyl)alanine to the genetic code of E. coli. J. Am. 5 53. Xu, R. et al. Site-specific incorporation of the mucin- Chem. Soc. 124, 1836–1837 (2002). at the nuclear envelope in mammalian cells . type N-acetylgalactosamine-α-O-threonine into protein 65. Turner, J. M., Graziano, J., Spraggon, G. & Schultz, P. G. It is assumed that most of these proteins in Escherichia coli. J. Am. Chem. Soc. 126, Structural characterization of a p-acetylphenylalanyl 4 15654–15655 (2004). aminoacyl-tRNA synthetase. J. Am. Chem. Soc. 127, interact directly or indirectly with lamins . 54. Lu, W., Gong, D., Bar-Sagi, D. & Cole, P. A. Site-specific 14976–14977 (2005). Among these nuclear membrane proteins are incorporation of a phosphotyrosine mimetic reveals a 66. Turner, J. M., Graziano, J., Spraggon, G. & Schultz, P. G. role for tyrosine phosphorylation of SHP-2 in cell Structural plasticity of an aminoacyl-tRNA synthetase three families, each of which is characterized signaling. Mol. Cell 8, 759–769 (2001). active site. Proc. Natl Acad. Sci. USA 103, 6483–6488 by a distinct motif (specifically, LEM, SUN or 55. Xie, J. Adding Unnatural Amino Acids to the Genetic (2006). Repertoire. Thesis, Scripps Research Institute, La Jolla 67. Tian, F., Tsao, M. L. & Schultz, P. G. A phage display KASH). LEM-domain proteins (named after (2006). system with unnatural amino acids. J. Am. Chem. Soc. LAP2, emerin and MAN1) are reviewed else- 56. Wang, J., Xie, J. & Schultz, P. G. A genetically encoded 126, 15962–15963 (2004). 4 fluorescent amino acid. J. Am. Chem. Soc. 128, 68. Castelli, D. D., Lovera, E., Ascenzi, P. & Fasano, M. where . We will discuss proteins that contain 8738–8739 (2006). Unfolding of the loggerhead sea turtle (Caretta caretta) the SUN domain and their partners, many 57. Summerer, D. et al. A genetically encoded fluorescent myoglobin: a 1H-NMR and electronic absorbance study. amino acid. Proc. Natl Acad. Sci. USA 103, Protein Sci. 11, 2273–2278 (2002). of which contain the KASH (named after 9785–9789 (2006). Klarsicht, ANC-1 and SYNE1 homology) 58. Tsao, M. L., Summerer, D., Ryu, Y. & Schultz, P. G. The Acknowledgements 6–8 genetic incorporation of a distance probe into proteins Work in the laboratory of P.G.S. is supported by the National domain . in Escherichia coli. J. Am. Chem. Soc. 128, Institutes of Health, the United States Department of Energy Most (but not all) SUN-domain proteins 4572–4573 (2006). and the Skaggs Institute for Chemical Biology. 59. Xie, J. et al. The site-specific incorporation of p-iodo-L- are localized at the INM. The situation is phenylalanine into proteins for structure determination. Competing interests statement more complicated for KASH-domain pro- Nature Biotechnol. 22, 1297–1301 (2004). The authors declare no competing financial interests. 60. Deiters, A., Geierstanger, B. H. & Schultz, P. G. Site- teins, most individual isoforms of which are 8,9 specific in vivo labeling of proteins for NMR studies. DATABASES localized on either the ONM or the INM . Chembiochem 6, 55–58 (2005). The following terms in this article are linked online to: 61. Suydam, I. T. & Boxer, S. G. Vibrational Stark effects However, some isoforms lack the KASH UniProtKB: http://ca.expasy.org/sprot calibrate the sensitivity of vibrational probes for electric ClpB | Gal4 | GRB2 | LamB | STAT1 domain, do not localize to the nuclear fields in proteins. Biochemistry 42, 12050–12055 (2003). FURTHER INFORMATION envelope and are instead proposed to 62. Alfonta, L., Zhang, Z., Uryu, S., Loo, J. A. & Schultz, P. G. Peter G. Schultz’s homepage: tether other organelles to the cytoskeleton8. Site-specific incorporation of a redox-active amino acid http://schultz.scripps.edu Several INM-localized SUN-domain and into proteins. J. Am. Chem. Soc. 125, 14662–14663 Access to this links box is available online. (2003). KASH-domain proteins can interact with lamins, and in certain cases this interaction is required for their nuclear envelope localiz ation (see below). OPINION This perspective will focus primarily on SUN-domain proteins: we will depict their structural organization (known and hypo- SUN-domain proteins: ‘Velcro’ that thetical) in complexes that traverse the nuclear envelope, and discuss their roles links the nucleoskeleton to the in nuclear positioning, centrosome attach- ment to the ONM, links to the cytoskeleton, cytoskeleton and telomere positioning during meiosis. We will propose a model in which SUN- domain proteins serve as mechanical ‘Velcro’ Yonatan B. Tzur, Katherine L. Wilson and Yosef Gruenbaum to interconnect the cytoskeleton and nucle- Abstract | The novel SUN-domain family of nuclear envelope proteins interacts with oskeleton, and suggest that SUN-domain proteins have further, non-mechanical roles various KASH-domain partners to form SUN-domain-dependent ‘bridges’ across as specialized nuclear envelope receptors. the inner and outer nuclear membranes. These bridges physically connect the nucleus to every major component of the cytoskeleton. SUN-domain proteins have SUN-domain and KASH-domain proteins diverse roles in nuclear positioning, centrosome localization, germ-cell Both the SUN domain and regions that are development, telomere positioning and apoptosis. By serving both as mechanical upstream of the SUN domain interact directly with the KASH domain of KASH-domain adaptors and nuclear envelope receptors, we propose that SUN-domain proteins proteins10,11. This interaction is required for connect cytoplasmic and nucleoplasmic activities. the cellular functions of both types of protein. For a discussion of the SUN-domain (Sad1 pore complexes, which control the traffic of Domain organization of SUN-domain and UNC-84 homology domain) family macro molecules between the nucleoplasm proteins. Malone and colleagues12 coined the of proteins, we must first introduce the and the cytoplasm. In metazoans, the nuclear term SUN domain when they discovered a nuclear envelope. In all eukaryotic cells, pore complexes and the INM are anchored motif of ~120 residues in the C terminus of the nuclear envelope separates the nucleus to a structural network of lamin filaments1 the Caenorhabditis elegans UNC-84 protein. from the cytoplasm. The nuclear envelope (BOX 1). Lamin polymers confer mechanical This protein has significant homology to a is composed of an outer nuclear membrane strength to the nucleus2,3. Many nuclear region in the Schizosaccharomyces pombe (ONM) and an inner nuclear membrane membrane and nucleoplasmic proteins Sad1 protein and several uncharacterized (INM). The two membranes join at nuclear interact with lamins4, and lamin-associated mammalian proteins. Genome-database 782 | OCTOBER 2006 | VOLUME 7 www.nature.com/reviews/molcellbio © 2006 Nature Publishing Group PERSPECTIVES searches indicated that UNC-84 is conserved Box 1 | The lamins and that the number of SUN-domain proteins has increased over the course of Lamins are type-V intermediate filament proteins. They are the main structural constituents of the metazoan nuclear lamina, a protein meshwork that lies between the inner nuclear membrane and evolution (FIG. 1). For example, the S. pombe chromatin. Lamins are also present in the nucleoplasm1,48. Lamins are divided into A and B types on genome contains a single SUN-domain the basis of their expression patterns and protein structure. B-type lamins are essential proteins gene, whereas C. elegans and Drosophila that are encoded by two genes in mammals (LMNB1 and LMNB2) and are present in all metazoan melanogaster each have two, and mammals cells. By contrast, A-type lamins (for example, lamin A and C) are derived by alternative splicing of a have at least four SUN-domain genes, SUN1, single gene (LMNA in human) that is found only in more complex metazoans; this gene is expressed SUN2, SUN3 and SPAG4 (REF. 8). mainly in differentiated cells and is not essential for cell viability49. B-type lamins and lamin A (but Besides the SUN domain, members of not lamin C) are translated as precursors with a C-terminal CAAX motif. The cysteine residue in the this family share other structural features CAAX motif is farnesylated, the last three residues (AAX) are subsequently removed by a zinc- to varying extents (FIG. 2). Most SUN- metalloprotease and the cysteine is then methyl-esterified. To produce mature lamin A, the last 15 domain proteins have at least one predicted residues are then cleaved by the zinc-metalloprotease Zmste24 (REF. 50). 2,3 transmembrane domain. Several span Lamin polymers confer mechanical strength to the nucleus . Lamins also interact with many different nuclear proteins51 and are involved in chromatin organization, DNA replication, the membrane multiple times, which is a transcription, assembly and disassembly of the nuclear envelope, spacing of nuclear pore potentially useful property for proteins that complexes and apoptosis52. Mutations in the human LMNA gene affect muscle, adipose, bone, are proposed to anchor mechanical-load- nerve and skin cells and are responsible for at least 12 heritable diseases, collectively termed bearing structures and transmit mechanical laminopathies, that include muscular dystrophies and premature ageing49,53,54. force. Human SUN1 spans the membrane three times13. SUN1 has an additional hydro- phobic region that is conserved in SUN2, but is not membrane inserted in either protein; Enaptin), Nesprin-2 (also known as syne-2 cells, most tested endogenous SUN-domain the function of this hydrophobic region and NUANCE) and Nesprin-3 genes in mam- proteins localize at the nuclear envelope is unknown13,20.
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