Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin (original) (raw)
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Review: Nuclear Lamins—Structural Proteins with Fundamental Functions
Journal of Structural Biology, 2000
The nuclear lamina is located between the inner nuclear membrane and the peripheral chromatin. It is composed of both peripheral and integral membrane proteins, including lamins and lamina-associated proteins. Lamins can interact with one another, with lamina-associated proteins, with nuclear scaffold proteins, and with chromatin. Likewise, most of the lamina-associated proteins are likely to interact directly with chromatin. The nuclear lamina is required for proper cell cycle regulation, chromatin organization, DNA replication, cell differentiation, and apoptosis. Mutations in proteins of the nuclear lamina can disrupt these activities and cause genetic diseases. The structure and assembly of the nuclear lamina proteins and their roles in chromatin organization and cell cycle regulation were recently reviewed. In this review, we discuss the roles of the nuclear lamina in DNA replication and apoptosis and analyze how mutations in nuclear lamina proteins might cause genetic diseases. 2000
Nuclear lamins: key regulators of nuclear structure and activities
Journal of Cellular and Molecular Medicine, 2009
The nuclear lamina is a proteinaceous structure located underneath the inner nuclear membrane (INM), where it associates with the peripheral chromatin. It contains lamins and lamin-associated proteins, including many integral proteins of the INM, chromatin modifying proteins, transcriptional repressors and structural proteins. A fraction of lamins is also present in the nucleoplasm, where it forms stable complexes and is associated with specific nucleoplasmic proteins. The lamins and their associated proteins are required for most nuclear activities, mitosis and for linking the nucleoplasm to all major cytoskeletal networks in the cytoplasm. Mutations in nuclear lamins and their associated proteins cause about 20 different diseases that are collectively called 'laminopathies'. This review concentrates mainly on lamins, their structure and their roles in DNA replication, chromatin organization, adult stem cell differentiation, aging, tumorogenesis and the lamin mutations leading to laminopathic diseases. Lamins are type V intermediate filaments (IFs) and like all members of the IF family of proteins, they have the tripartite domain organization of a central ␣ helical rod domain, flanked by a short head and a longer tail domains (Fig. 1A). The rod domain is made of four coiled-coil segments: 1A, 1B, 2A and 2B, each of which is made of heptad repeats. The coiled-coil segments are linked by three linkers termed L1, L12 and L2, which are conserved in length and sequence among lamins [1, 2]. The end segments of the central rod domain (~30 amino acids on both
The nuclear lamins are members of the intermediate filament (IF) family of proteins. The lamins have an essential role in maintaining nuclear integrity, as do the other IF family members in the cytoplasm. Also like cytoplasmic IFs, the organization of lamins is dynamic. The lamins are found not only at the nuclear periphery but also in the interior of the nucleus, as distinct nucleoplasmic foci and possibly as a network throughout the nucleus. Nuclear processes such as DNA replication may be organized around these structures. In this review, we discuss changes in the structure and organization of the nuclear lamins during the cell cycle and during cell differentiation. These changes are correlated with changes in nuclear structure and function. For example, the interactions of lamins with chromatin and nuclear envelope components occur very early during nuclear assembly following mitosis. During S-phase, the lamins colocalize with markers of DNA replication, and proper lamin organization must be maintained for replication to proceed. When cells differentiate, the expression pattern of lamin isotypes changes. In addition, changes in lamin organization and expression patterns accompany the nuclear alterations observed in transformed cells. These lamin structures may modulate nuclear function in each of these processes.
A chromatin binding site in the tail domain of nuclear lamins that interacts with core histones
Journal of Cell Biology, 1995
Interaction of chromatin with the nuclear envelope and lamina is thought to help determine higher order chromosome organization in the interphase nucleus. Previous studies have shown that nuclear lamins bind chromatin directly. Here we have localized a chromatin binding site to the carboxyl-terminal tail domains of both A-and B-type mammalian lamins, and have characterized the biochemical properties of this binding in detail. Recombinant glutathione-S-transferase fusion proteins containing the tail domains of mammalian lamins C, BI, and B 2 were analyzed for their ability to associate with rat liver chromatin fragments immobi-lized on microtiter plate wells. We found that all three lamin tails specifically bind to chromatin with apparent Kds of 120-300 nM. By examining a series of deletion mutants, we have mapped the chromatin binding region of the lamin C tail to amino acids 396--430, a segment immediately adjacent to the rod domain. Furthermore, by analysis of chromatin subfractions, we found that core histones constitute the principal chromatin binding component for the lamin C tail. Through cooperativity, this lamin-histone interaction could be involved in specifying the high avidity attachment of chromatin to the nuclear envelope in vivo. T HE nuclear lamina is a filamentous protein meshwork that lines the nucleoplasmic surface of the nuclear envelope (NE) 1 (reviewed by . The lamina is thought to provide a structural framework for the NE and an anchoring site at the nuclear periphery for interphase chromosomes, and therefore could play a major role in interphase nuclear organization. The lamina consists of a polymeric assembly of nuclear lamins, members of the intermediate filament (IF) protein superfamily (see , as well as a number of less abundant lamina-associated polypeptides (discussed by . Vertebrate lamins are classified as A-or B-subtypes based on their sequence and biochemical properties. B-type lamins (lamins B1 and B2) are present in somatic cells throughout development, while A-type lamins (lamins A and C) are expressed only during or after terminal differentiation in most cells. Mam-
Lamins A and C but Not Lamin B1 Regulate Nuclear Mechanics
Journal of Biological Chemistry, 2006
Mutations in the nuclear envelope proteins lamins A and C cause a broad variety of human diseases, including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. Cells lacking lamins A and C have reduced nuclear stiffness and increased nuclear fragility, leading to increased cell death under mechanical strain and suggesting a potential mechanism for disease. Here, we investigated the contribution of major lamin subtypes (lamins A, C, and B1) to nuclear mechanics by analyzing nuclear shape, nuclear dynamics over time, nuclear deformations under strain, and cell viability under prolonged mechanical stimulation in cells lacking both lamins A and C, cells lacking only lamin A (i.e."lamin C-only" cells), cells lacking wild-type lamin B1, and wild-type cells. Lamin A/C-deficient cells exhibited increased numbers of misshapen nuclei and had severely reduced nuclear stiffness and decreased cell viability under strain. Lamin C-only cells had slightly abnormal nuclear shape and mildly reduced nuclear stiffness but no decrease in cell viability under strain. Interestingly, lamin B1-deficient cells exhibited normal nuclear mechanics despite having a significantly increased frequency of nuclear blebs. Our study indicates that lamins A and C are important contributors to the mechanical stiffness of nuclei, whereas lamin B1 contributes to nuclear integrity but not stiffness. Lamins are type V intermediate filament proteins that form the nuclear lamina, a filamentous network underlying the inner nuclear membrane of eukaryotic cells. Lamins form stable structures in the nuclear lamina and the nucleoplasm, determine nuclear shape and size, resist nuclear deformation, and position nuclear pore complexes (reviewed in Refs. 1-3
Partners and post-translational modifications of nuclear lamins
Chromosoma, 2013
Nuclear intermediate filament networks formed by A-and B-type lamins are major components of the nucleoskeleton that are required for nuclear structure and function, with many links to human physiology. Mutations in lamins cause diverse human diseases ('laminopathies'). At least fiftyfour partners interact with human A-type lamins directly or indirectly. The less studied human lamins B1 and B2 have twenty-three and seven reported partners, respectively. These interactions are likely to be regulated at least in part by lamin post-translational modifications. This review summarizes the binding partners and post-translational modifications of human lamins and discusses their known or potential implications for lamin function.
Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins
Proceedings of the National Academy of Sciences, 2008
Lamins are nuclear intermediate filament proteins and the major building blocks of the nuclear lamina. Besides providing nuclear shape and mechanical stability, lamins are required for chromatin organization, transcription regulation, DNA replication, nuclear assembly, nuclear positioning, and apoptosis. Mutations in human lamins cause many different heritable diseases, affecting various tissues and causing early aging. Although many of these mutations result in nuclear deformation, their effects on lamin filament assembly are unknown. Caenorhabditis elegans has a single evolutionarily conserved lamin protein, which can form stable 10-nmthick filaments in vitro. To gain insight into the molecular basis of lamin filament assembly and the effects of laminopathic mutations on this process, we investigated mutations in conserved residues of the rod and tail domains that are known to cause various laminopathies in human. We show that 8 of 14 mutant lamins present WT-like assembly into filaments or paracrystals, whereas 6 mutants show assembly defects. Correspondingly, expressing these mutants in transgenic animals shows abnormal distribution of Ce-lamin, abnormal nuclear shape or change in lamin mobility. These findings help in understanding the role of individual residues and domains in laminopathy pathology and, eventually, promote the development of therapeutic interventions. filament assembly ͉ laminopathic diseases ͉ nuclear envelope