Direct Interaction between Emerin and Lamin A
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Emerin
Nuclear lamina
Inner membrane
The nuclear envelope is composed of the nuclear lamina, nuclear pore complexes and nuclear membranes. The outer nuclear membrane is very similar to the rough endoplasmic reticulum. The pore membranes contain unique integral proteins and are associated with nuclear pore complexes. The inner nuclear membrane is associated with heterochromatin and the nuclear lamina, a meshwork of intermediate filament proteins called lamins. In humans, lamins are encoded by three genetic loci, LMNA, LMNB1 and LMNB2. Mutations in LMNA cause a spectrum of inherited diseases, including autosomal dominant Emery-Dreifuss muscular dystrophy and related striated muscle disorders, partial lipodystrophies, a peripheral neuropathy and progeria syndromes. Eighty or more transmembrane proteins may reside primarily in the inner nuclear membrane but only several have been fairly well characterized. These include emerin, which is mutated in X-linked Emery-Dreifuss muscular dystrophy, LAP2, MAN1 and LBR. LBR binds to B-type lamins and chromatin proteins and shares sequence similarities with sterol reductases. Heterozygous mutations in LBR cause Pelger-Huët anomaly, characterized by morphologically abnormal neutrophil nuclei, and homozygous mutations cause HEM/Greenberg skeletal dysplasia, characterized by developmental abnormalities and 3 β-hydroxysterol-δ-14-reductase deficiency. Further studies of nuclear envelope proteins may uncover additional unsuspected relationships to human disease.
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Nuclear pores are sophisticated gateways on the nuclear envelope that control macromolecular transport between the cytoplasm and nucleoplasm. So far the structural and functional aspects of nuclear pores have been extensively studied, but their distribution and density, which might reflect nuclear organization and function, remain unknown. Here, we report the cell-cycle-dependent dynamics of nuclear pores. Large distinct subdomains lacking nuclear pores are present on the nuclear surface of HeLaS3 cells in early cell-cycle stages. Such ;pore-free islands' gradually become dispersed in G1-S phase. Surprisingly, the islands are enriched with inner nuclear membrane proteins lamin A/C and emerin, but exclude lamin B. Lamin-A/C-enriched pore-free islands were also observed in human normal diploid fibroblasts and several cell lines, showing the generality of this phenomenon. Knockdown and ectopic expression analyses demonstrated that lamin A/C, but not emerin, plays an essential structural and regulatory role in the nuclear pore distribution and the formation of pore-free islands. These data thus provide strong evidence that the dynamics of nuclear pores are regulated by the reorganization of inner nuclear structures.
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ADLD=
: adult-onset autosomal dominant leukodystrophy;
CMT=
: Charcot-Marie-Tooth;
EDMD=
: Emery-Dreifuss muscular dystrophy;
LAP=
: lamin-associated polypeptide;
LBR=
: lamin B receptor;
LGMD1B=
: autosomal dominant limb-girdle muscular dystrophy
The nuclear envelope is the interface between the nucleus and the rest of the cell and consists of inner and outer nuclear membranes. The nuclear lamina underlies the inner nuclear membrane and is an essential structural element of the nuclear envelope. The nuclear lamina maintains the nuclear architecture and regulates DNA replication and chromatin organization. The major components of the nuclear lamina are the nuclear lamins, including lamin A/C and lamin B. Lamins interact with several other inner nuclear proteins, such as emerin; these interactions are critical for the functional organization of chromatin, transport across the nuclear envelope, and transmission of mechanical signals to the nucleus. Mutations in genes encoding lamins and their associated proteins cause a wide spectrum of diseases called “laminopathies.” Mutations affecting lamin A or associated proteins, such as emerin, produce Emery-Dreifuss muscular dystrophy (EDMD). LMNA mutations also produce autosomal dominant limb-girdle muscular dystrophy (LGMD1B) and Charcot-Marie-Tooth (CMT) disease type 2B1. Duplication in LMNB1 , encoding lamin B1, causes autosomal dominant leukodystrophy. Lamin mutations have also been linked to cardiomyopathy, lipodystrophy, and accelerated aging disorders. The functional organization of the nuclear envelope and the wide spectrum of laminopathies have been the subject of several recent reviews.1,–,7
The principal components of the nuclear envelope are the inner and outer nuclear membranes, separated by the perinuclear space4,8 (figure). The outer nuclear membrane is contiguous with and functionally related …
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Abstract Lamin-associated proteins (LAP) comprise a group of polypeptides localized at the inner nuclear membrane which interact stably with nuclear lamins. The three lamin-associated proteins that have been characterized in detail, LAP1, LAP2, and LBR, are all integral membrane proteins, and have potential roles in the attachment of nuclear lamins and/or chromatin to the inner nuclear membrane.1 Another integral membrane protein, emerin, has recently been demonstrated to be a LAP.24
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Since the discovery of the inner nuclear transmembrane protein emerin in the early 1990s, nuclear envelope (NE) components and related involvement in nuclei integrity and functionality have been highly investigated. The NE is composed of two distinct lipid bilayers described as the inner (INM) and outer (ONM) nuclear membrane. Nuclear envelope proteins can be specifically "integrated" in the INM (such as emerin and SUN proteins) or in the ONM such as nesprins. Additionally, flanked to the INM, the nuclear lamina, a proteinaceous meshwork mainly composed of lamins A and C completes NE composition. This network of proteins physically interplays to guarantee NE integrity and most importantly, shape the bridge between cytoplasmic cytoskeletons networks (such as microtubules and actin) and the genome, through the anchorage to the heterochromatin. The essential network driving the connection of nucleoskeleton with cytoskeleton takes place in the perinuclear space (the space between ONM and INM) with the contribution of the LINC complex (for LInker of Nucleoskeleton to Cytoskeleton), hosting KASH and SUN proteins interactions. This close interplay between compartments has been related to diverse functions from nuclear integrity, activity and positioning through mechanotransduction pathways. At the same time, mutations in NE components genes coding for proteins such as lamins or nesprins, had been associated with a wide range of congenital diseases including cardiac and muscular diseases. Although most of these NE associated proteins are ubiquitously expressed, a large number of tissue-specific disorders have been associated with diverse pathogenic mutations. Thus, diagnosis and molecular explanation of this group of diseases, commonly called "nuclear envelopathies", is currently challenging. This review aims, first, to give a better understanding of diverse functions of the LINC complex components, from the point of view of lamins and nesprins. Second, to summarize human congenital diseases with a special focus on muscle and heart abnormalities, caused by mutations in genes coding for these two types of nuclear envelope associated proteins.
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Loss of a-Type Lamin Expression Compromises Nuclear Envelope Integrity Leading to Muscular Dystrophy
The nuclear lamina is a protein meshwork lining the nucleoplasmic face of the inner nuclear membrane and represents an important determinant of interphase nuclear architecture. Its major components are the A- and B-type lamins. Whereas B-type lamins are found in all mammalian cells, A-type lamin expression is developmentally regulated. In the mouse, A-type lamins do not appear until midway through embryonic development, suggesting that these proteins may be involved in the regulation of terminal differentiation. Here we show that mice lacking A-type lamins develop to term with no overt abnormalities. However, their postnatal growth is severely retarded and is characterized by the appearance of muscular dystrophy. This phenotype is associated with ultrastructural perturbations to the nuclear envelope. These include the mislocalization of emerin, an inner nuclear membrane protein, defects in which are implicated in Emery-Dreifuss muscular dystrophy (EDMD), one of the three major X-linked dystrophies. Mice lacking the A-type lamins exhibit tissue-specific alterations to their nuclear envelope integrity and emerin distribution. In skeletal and cardiac muscles, this is manifest as a dystrophic condition related to EDMD.
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Nuclear lamina
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Nuclear shape changes are observed during a variety of developmental processes, pathological conditions, and ageing. The mechanisms underlying nuclear shape changes in the above-mentioned situations have mostly remained unclear. To address the molecular mechanism behind nuclear shape changes, we analyzed how the farnesylated nuclear envelope proteins Kugelkern and lamin Dm0 affect the structure of the nuclear membrane. We found that Kugelkern and lamin Dm0 affect nuclear shape without requiring filament formation or the presence of a classical nuclear lamina. We also could show that the two proteins do not depend on a group of selected inner nuclear membrane proteins for their localization to the nuclear envelope. Surprisingly, we found that farnesylated Kugelkern and lamin Dm0 protein constructs change the morphology of protein-free liposomes. Based on these findings, we propose that farnesylated proteins of the nuclear membrane induce nuclear shape changes by being asymmetrically inserted into the phospholipid bilayer via their farnesylated C-terminal part.
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