Nesprins: intracellular scaffolds that maintain cell architecture and coordinate cell function?

Abstract

Nesprins are a recently discovered family of ubiquitously expressed intracellular proteins. Through alternative transcriptional initiation, termination and splicing, two genes - nesprin-1 and nesprin-2 (also known as syne-1 and syne-2) - give rise to many protein isoforms that vary markedly in size. The largest of these isoforms comprise a C-terminal transmembrane domain (the KLS domain) linked by a spectrin-repeat rod domain to an N-terminal paired, actin-binding, calponin-homology domain. This structure suggests that they are well suited to orchestrate signalling between cell membranes and the cytoskeleton. Other isoforms have variable lengths of this rod domain linked to either end of the protein. Smaller isoforms with the KLS domain are localised at the inner nuclear membrane, where they bind lamin A/C and emerin. Larger nesprin isoforms link the outer nuclear membrane with intracellular organelles and the actin cytoskeleton and are thought to regulate nuclear anchorage and organelle migration. Thus, nesprins might have a variety of fundamental roles in cells, particularly muscle cells where they are highly expressed. We speculate that nesprin mutations might contribute to a broad range of human disease syndromes, including laminopathies.

Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness

“…Several isoforms of Nesprin 1 (also called Syne1 [18], Myne1 [19], and Enaptin [20]) and Nesprin 2 (also called Syne2 [18] and NUANCE [21]) are encoded by the alternative transcription and splicing of two distinct genes [22]. Nesprins are characterized by a variable number of spectrin repeats and most isoforms share a conserved C-terminal KASH domain (Klarsicht-Ancl-Syne1 Homology) comprising ∼50 amino acids.…”

Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin

“…The mammalian nesprins [Nesprin-1 (also known as Syne1, Myne-1 and Enaptin), Nesprin-2 (also known as Syne2, Myne-2 and NUANCE) and and their single-gene-encoded orthologues (interaptin in Dictyostelium discoideum, ANC-1 in Caenorhabditis elegans and MSP-300 in Drosophila melanogaster) represent a novel class of broadly expressed multifunctional proteins (Starr and Han, 2002;Warren et al, 2005), anchored in the nuclear membrane through their highly conserved C-terminal KASHdomain Starr and Fischer, 2005;Tzur et al, 2006).…”

“…The multitude of subcellular nesprin localizations and isoform diversity suggests, however, additional functions. Indeed Nesprin-1 and Nesprin-2 isoforms localize at plasma membrane foci, mitochondria, sarcomeric structures, Golgi complexes, the nucleoplasm, and the outer and inner nuclear membrane, where they associate directly with emerin and lamin A/C Mislow et al, 2002a;Mislow et al, 2002b;Warren et al, 2005;Zhang et al, 2005).…”

Experimental techniques for study of chromatin mechanics in intact nuclei and living cells

“…Many of the major discoveries in this field were first made in C. elegans and Drosophila, and then subsequently found to be conserved in vertebrates. In the current model (see Warren et al 2005, Stewart et al 2007 for detailed reviews), nuclear lamins and other nuclear envelope proteins interact with SUN family proteins located at the inner nuclear membrane (Worman & Gundersen 2006, Ketema et al 2007, Liu et al 2007, Wheeler et al 2007. SUN proteins in turn associate across the luminal space with the KASH domain of nesprins residing on the outer nuclear membrane (Padmakumar et al 2005, Crisp et al 2006.…”

“…Nesprins are encoded by at least three different genes and are found in many splicing variants. Nesprins are spectrin-repeat-containing proteins that are anchored to the outer nuclear membrane through their C-terminal KASH domain (Warren et al 2005). Different nesprin subtypes contain N-terminal cytoplasmic binding domains for direct interaction with specific cytoskeletal structures, e.g.…”