title: The nesprins are giant actin-binding proteins, orthologous to Drosophila melanogaster muscle protein MSP-300.
abstract: Nesprin-1 and nesprin-2 (also known as Syne-1 and Syne-2,) are large ( approximately 3300-residue) vertebrate proteins associated with emerin and lamin A at the nuclear envelope of muscle cells and other cell types. We show that the previously described nesprins are short isoforms of giant proteins comprising an actin-binding amino-terminus connected to a carboxy-terminal klarsicht-related transmembrane domain by a massive ( approximately 6000-8000 amino acid) spectrin-like rod domain, making full-length nesprin-1, at one megadalton, the largest non-titin protein hitherto described in humans. We find that MSP-300, a 7000-residue Drosophila melanogaster protein whose disruption results in defects of muscle development, corresponds to the N-terminal two-thirds of the Drosophila nesprin ortholog. A nesprin-like protein is also encoded by the nematode genome. Moreover, we demonstrate that the larger isoforms of nesprin-1, like MSP-300, are localized to the sarcomeric Z-line of both skeletal and cardiac muscle. The recognition that a characteristic muscle-specific mutant phenotype in the fly results from a disruption of its nesprin ortholog reinforces the candidacy of the human proteins for involvement in genetic diseases of skeletal and cardiac muscle.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Box 110, Cambridge, CB2 2QQ, UK.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Zhang
authors.forename: Cassandra
authors.initials: C
authors.lastname: Ragnauth
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Greener
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.forename: Roland G
authors.initials: RG
authors.lastname: Roberts
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000166:cytology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009348:Nematoda; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010802:Phylogeny; D020033:Protein Isoforms; D016415:Sequence Alignment; D013347:Subcellular Fractions
chemical_list: D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; C079806:Msp300 protein, Drosophila; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C415465:SYNE1 protein, human; C485904:SYNE2 protein, human