LINC'ing form and function at the nuclear envelope

Abstract

a b s t r a c tThe nuclear envelope is an amazing piece of engineering. On one hand it is built like a mediaeval fortress with filament systems reinforcing its membrane walls and its double membrane structure forming a lumen like a castle moat. On the other hand its structure can adapt while maintaining its integrity like a reed bending in a river. Like a fortress it has guarded drawbridges in the nuclear pore complexes, but also has other mechanical means of communication. All this is enabled largely because of the LINC complex, a multi-protein structure that connects the intermediate filament nucleoskeleton across the lumen of the double membrane nuclear envelope to multiple cytoplasmic filament systems that themselves could act simultaneously both like mediaeval buttresses and like lines on a suspension bridge. Although many details of the greater LINC structure remain to be discerned, a number of recent findings are giving clues as to how its structural organization can yield such striking dynamic yet stable properties. Combining double-and triple-helical coiled-coils, intrinsic disorder and order, tissue-specific components, and intermediate filaments enables these unique properties.

A Special Topic on Nuclear Mechanobiology

“…1,14,17 First identified in 2005 by Crisp et al, the LINC complex consists of a series of proteins containing KASH-domain and SUN-domain proteins, which reside in the outer and inner nuclear membranes, respectively. 7,18 This evolutionarily conserved molecular bridge is known to transmit spatial, structural and mechanical information across from the cytoskeleton to the nucleoskeleton. 6,10,16 Numerous diseases have been shown to be associated with mutations in LINC complex proteins, typically in structural and mechanical tissues such as muscle.…”

Nuclear pore complex tethers to the cytoskeleton

“…It is therefore not surprising that it should have a dominant influence, as well as be used as a platform, for determining cell architecture and function. The LINC complex (LInker of Nucleoskeleton and Cytoskeleton) is the best known anchor of cell architecture to the nucleus (Meinke et al, 2015). It contains SUN domain proteins which are integral membrane proteins, primarily of the inner nuclear membrane, which interact with the nuclear lamina, chromatin and other "nucleoskeletal" structures.…”

LINCing Defective Nuclear-Cytoskeletal Coupling and DYT1 Dystonia

“…The LINC (linker of nucleoskeleton and cytoskeleton) complex is an evolutionarily conserved molecular bridge in the nuclear envelope (NE) that is responsible for physically coupling the nucleus to the cytoskeleton in most eukaryotic cells 1 . LINC complexes are composed of two type II membrane proteins: the ONM (outer nuclear membrane) KASH ( Klarsicht, ANC-1 , and Syne homology) proteins and the INM (inner nuclear membrane) SUN ( Sad1 and UNC-84 ) proteins 2 .…”

“…Within the perinuclear space, KASH proteins directly interact with the conserved SUN domain of SUN proteins through their lumenal KASH domain 4 . The divergent SUN protein C-terminus extends into the nucleoplasm, where it interacts with A-type lamins, chromatin-binding proteins, and other proteins 1 . It is through the KASH-SUN interaction that the LINC complex is able to transmit mechanical forces from the cytoplasm across the double membrane of the NE and into the nucleoplasm.…”

“…Over the past decade, the LINC complex has attracted much attention resulting in the identification of a growing list of KASH and SUN proteins, LINC complex accessory proteins, as well as LINC complex-dependent cellular functions including DNA damage repair, meiotic pairing of homologous chromosomes, mechanotransduction, and nuclear positioning 1, 3, 7 . In light of this wide range of cellular and developmental functions that rely upon LINC complex-dependent nuclear-cytoskeletal coupling, it should come as no surprise that mutations in the genes encoding KASH and SUN proteins are associated with an ever-expanding list of human diseases including ataxia, cancer, deafness, and muscular dystrophy.…”