title: Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle.
abstract: Nesprin-2 is a multi-isomeric, modular protein composed of variable numbers of spectrin-repeats linked to a C-terminal transmembrane domain and/or to N-terminal paired calponin homology (CH) domains. The smaller isoforms of nesprin-2 co-localize with and bind lamin A and emerin at the inner nuclear envelope (NE). In SW-13 cells, which lack lamin A/C, nesprin-2 epitopes and emerin were both mislocalized and formed aggregates in the endoplasmic reticulum (ER). The larger isoforms and other CH-domain-containing isoforms co-localize with heterochromatin within the nucleus and are also present at the outer NE and in multiple cytoplasmic compartments. Nesprin-2 isoforms relocalize during in vitro muscle differentiation of C2C12 myoblasts to the sarcomere of myotubes. Immunogold electron microscopy using antibodies specific for three different epitopes detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. In adult skeletal muscle, confocal immunolocalization studies demonstrated that nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. These data suggest that nesprin-2 isoforms form a linking network between organelles and the actin cytoskeleton and thus may be important for maintaining sub-cellular spatial organisation. Moreover, its association at the NE with lamin and emerin, the genes mutated in Emery-Dreifuss muscular dystrophy, suggests a mechanism to explain how disruption of the NE leads to muscle dysfunction.
authors.affiliation: Department of Medicine, ACCI, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Zhang
authors.forename: Cassandra D
authors.initials: CD
authors.lastname: Ragnauth
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Skepper
authors.forename: Nathalie F
authors.initials: NF
authors.lastname: Worth
authors.forename: Derek T
authors.initials: DT
authors.lastname: Warren
authors.forename: Roland G
authors.initials: RG
authors.lastname: Roberts
authors.forename: Peter L
authors.initials: PL
authors.lastname: Weissberg
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Ellis
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry; D017398:Alternative Splicing; D001665:Binding Sites; D002458:Cell Fractionation; D006801:Humans; D047468:Immunoprecipitation; D034882:Lamins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008840:Microfilament Proteins; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013946:Thymopoietins / Q000378:metabolism*
chemical_list: D034882:Lamins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C485904:SYNE2 protein, human; D013946:Thymopoietins; C092710:emerin