Abstract
The linker of nucleoskeleton and cytoskeleton (LINC) complex is composed of the outer and inner nuclear membrane protein families Klarsicht, Anc-1, and Syne homology (KASH), and Sad1 and UNC-84 (SUN) homology domain proteins. Increasing evidence has pointed to diverse functions of the LINC complex, such as in nuclear migration, nuclear integrity, chromosome movement and pairing during meiosis, and mechanotransduction to the genome. In metazoan cells, the nuclear envelope possesses the nuclear lamina, which is a thin meshwork of intermediate filaments known as A-type and B-type lamins and lamin binding proteins. Both of lamins physically interact with the inner nuclear membrane spanning SUN proteins. The nuclear lamina has also been implicated in various functions, including maintenance of nuclear integrity, mechanotransduction, cellular signalling, and heterochromatin dynamics. Thus, it is clear that the LINC complex and nuclear lamins perform diverse but related functions. However, it is unknown whether the LINC complex–lamins interactions are involved in these diverse functions, and their regulation mechanism has thus far been elusive. Recent structural analysis suggested a dynamic nature of the LINC complex component, thus providing an explanation for LINC complex organization. This review, elaborating on the integration of crystallographic and biochemical data, helps to integrate this research to gain a better understanding of the diverse functions of the LINC complex.
Highlights
The nuclear envelope (NE) is composed of the inner nuclear membrane (INM) and outer nuclear membrane (ONM), which are separated by a 40–50 nm perinuclear space (PNS) and spanned by the nuclear pore complex
Lamins play various roles such as maintenance of nuclear integrity, cell cycle regulation, mechanotransduction, cellular signalling, and DNA repair. Because all of these functions are critical for cell viability, variations in the expression or dysfunction of lamins and their interacting linker of nucleoskeleton and cytoskeleton (LINC) complexes are associated with a wide range of diseases, including muscular dystrophy, cardiomyopathies, lipodystrophy, progeria, cancer, and neurological diseases [37]
), which are necessary for SUN2 trimerization and KASH binding [40]
Summary
The nuclear envelope (NE) is composed of the inner nuclear membrane (INM) and outer nuclear membrane (ONM), which are separated by a 40–50 nm perinuclear space (PNS) and spanned by the nuclear pore complex. Lamins play various roles such as maintenance of nuclear integrity, cell cycle regulation, mechanotransduction, cellular signalling, and DNA repair Because all of these functions are critical for cell viability, variations in the expression or dysfunction of lamins and their interacting LINC complexes are associated with a wide range of diseases, including muscular dystrophy, cardiomyopathies, lipodystrophy, progeria, cancer, and neurological diseases [37]. One reason is that mammalian somatic cells express at least two SUN domain proteins, which have partially overlapping functions, and up to four KASH domain partners (i.e., nesprins 1–4). I discuss the possible functions of the dynamic interactions between SUN and lamins Integrating this recent insight with well-established knowledge of these interactions should help to provide a better foundation for elucidating the regulatory mechanisms of the LINC complex, and help to understand its cellular functions and roles in diseases
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