Inner nuclear membrane proteins (INM proteins) are membrane proteins that are embedded in or associated with the inner membrane of the nuclear envelope. There are about 60 INM proteins, most of which are poorly characterized with respect to structure and function. [2] Among the few well-characterized INM proteins are lamin B receptor (LBR), lamina-associated polypeptide 1 (LAP1), lamina-associated polypeptide-2 (LAP2), emerin and MAN1.
Several integral nuclear membrane proteins of different size and structure have been identified. [3] It is proposed that they share some structural features with respect to nucleoplasmic domain(s) and lipid-soluble domain(s). Some INM proteins contain common protein domain structures, and can thus be categorised into known protein domain families. These include the LEM-, SUN-, and KASH-domain families. Members of the LEM-domain family play a part in chromatin organisation. SUN- and KASH-domains participate in linking the cytoskeleton and nucleoskeleton through the LINC complex. [4]
Lamins and chromatin found at the nuclear envelope are organised with the assistance of proteins embedded in the INM. [5] INM proteins also aid in organization of nuclear pore complexes (NPCs). The protein mPom121 is targeted to the INM and is necessary for NPC formation. [3] Proteins containing the LEM domain, such as emerin, LAP2β and MAN1, seem to have a number of roles. They interact with the barrier-to-autointegration factor (BAF). [6] and help to repress gene expression, both by tethering specific genomic regions to the nuclear periphery, and by interaction with histone deacetylase (HDAC) 3. [7]
There are several proteins associated with the inner nuclear membrane. It is likely that the majority of them are also associated with the nuclear lamina. Some may interact directly with the nuclear lamina, and some may be associated with it through scaffold proteins. [3] All INM proteins are arranged such that their N-termini is facing the nucleoplasm and targeted by various kinases. [8] They are synthesized in one of three places; in the cytoplasm, the cytoplasmic ER, or the outer nuclear membrane. All require localisation to the INM. [4] Since the outer nuclear membrane is continuous with the endoplasmic reticulum it is possible that the inner nuclear membrane proteins are translated on the rough endoplasmic reticulum, whereby the proteins move into the nucleus by lateral diffusion through a nuclear pore. [3] In this model, proteins diffuse freely from the ER to the inner nuclear membrane, where association with nuclear lamina or chromatin immobilizes them. [9] A nuclear localisation signal is not sufficient to target a protein to the INM, and the N-terminal domain of LBR cannot translocate into the nuclear lumen if its size is increased from 22 to approximately 70 kDa, supporting this view. [10] Current opinion is that INM proteins synthesised in the cytoplasm are transported to the INM through nuclear pore complexes (NPC). [4]
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It has been proposed that chromatin-binding/modifying proteins embedded within the inner nuclear membrane may be central in determining the identity of newly differentiated cells. The nucleoplasmic domains of such proteins can interact with chromatin to create a scaffold and restrict the conformation of chromosomes within three dimensions. Such inner-nuclear-membrane proteins (INMs) may function simply by restricting the movement of bound chromatin, by recruiting chromatin-remodeling proteins, or through inherent enzyme activity. INM:chromatin interactions causes some segments of chromatin to be more exposed to the nucleoplasm than others.
Once INM:chromatin interactions have been established following formation of the nuclear envelope, soluble nuclear proteins may bind to exposed chromosomal segments. Such proteins could include enzymes that modify histones—such as methylases and acetylases—which act to alter the three-dimensional conformation of chromatin, as well as DNA binding proteins—such as helicases, gyrases, and transcription factors—that are involved in unwinding/looping DNA and/or recruiting RNAP holoenzyme. This will promote the transcription of some genes and down-regulate or prevent transcription of others. Thus, the nuclear scaffold places limits on what genes can and can not be expressed within a given cell and, hence, may serve a basis for cell identity.
Once all regulatory proteins, etc. have been synthesized and the scaffold has been established, the cell has attained its own specific expression profile. This allows it to synthesize cell-specific enzymes and receptors characteristic of its particular function. The nuclear scaffold is predicted to be relatively permanent for a given cell type, but induction of a signaling pathway—by ligand binding, cell:cell contact, or some other mechanism—can temporarily shift the expression profile. When such a signal changes expression of genes coding for INM or a chromatin-modifying enzymes, it can induce differentiation in to a different cell type. Thus, the Nuclear Scaffold Theory predicts that symmetric cell division occurs when a daughter cell contains the same complement of INMs as the parent cell. Conversely, asymmetric cell division is expected to result in parent and daughter cells with different INM profiles.
The INM profile of closely related cells (e.g., CD4+ TH1 and TH2 helper T-cells) is expected to be more similar than for cells that are more distantly related (e.g., T-cells and B-cells). The degree of INM complementarity is expected to be roughly proportional to the degree of relatedness (e.g., % complementarity to TH1 helper T-cells will be: TH2 > CD8+ > B-cell > Erythrocyte > cardiomyocyte). Some cells that are very closely related may have similar INMs, but transient changes in expression—e.g., in response to extracellular signals—could possibly lead to more permanent changes in expression profile by altering transcription rates for chromatin modifying enzymes, transcriptional modulators, or other regulatory proteins.
Posttranslational modifications of INM proteins play a critical role in their functional modulation. For example, lamin B receptor, lamina-associated polypeptide 1 and lamina-associated polypeptide 2 are targets for different protein kinases. [8] Arginine and serine residues phosphorylation control LBR's interaction with other subunits of the LBR complex and was proposed to modulate the interaction with chromatin. [12]
The wide array of diseases involving lamins and their associated inner nuclear membrane proteins are collectively called laminopathies. [13] Mutations in the gene EDM, encoding the INM protein emerin may be the cause of X-linked Emery–Dreifuss muscular dystrophy. [2] As mutations in lamins cause the autosomal dominant form of Emery–Dreifuss muscular dystrophy, and lamins and emerin are known to interact, it has been hypothesised that muscle disease is caused by a structural defect in the nuclear envelope brought on by dysfunction in one of these proteins. [1] Mutations in the gene LBR, encoding lamin B receptor, causes Pelger-Hüet anomaly. [14]
Tumor cells often show an aberrant nuclear structure, which is used by pathologists in diagnostics. As changes in the nuclear envelope correspond to functional changes in the nucleus, morphological changes in the nucleus may be involved in carcinogenesis. The regulatory functions of inner nuclear membrane proteins strongly suggest this possibility. [15]
In cell biology, the nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotes usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support, much like the cytoskeleton supports the cell as a whole.
Telophase is the final stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase are reversed. As chromosomes reach the cell poles, a nuclear envelope is re-assembled around each set of chromatids, the nucleoli reappear, and chromosomes begin to decondense back into the expanded chromatin that is present during interphase. The mitotic spindle is disassembled and remaining spindle microtubules are depolymerized. Telophase accounts for approximately 2% of the cell cycle's duration.
Lamins, also known as nuclear lamins are fibrous proteins in type V intermediate filaments, providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with inner nuclear membrane proteins to form the nuclear lamina on the interior of the nuclear envelope. Lamins have elastic and mechanosensitive properties, and can alter gene regulation in a feedback response to mechanical cues. Lamins are present in all animals but are not found in microorganisms, plants or fungi. Lamin proteins are involved in the disassembling and reforming of the nuclear envelope during mitosis, the positioning of nuclear pores, and programmed cell death. Mutations in lamin genes can result in several genetic laminopathies, which may be life-threatening.
The nuclear lamina is a dense fibrillar network inside the nucleus of eukaryote cells. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lamina regulates important cellular events such as DNA replication and cell division. Additionally, it participates in chromatin organization and it anchors the nuclear pore complexes embedded in the nuclear envelope.
In biology, the nuclear matrix is the network of fibres found throughout the inside of a cell nucleus after a specific method of chemical extraction. According to some it is somewhat analogous to the cell cytoskeleton. In contrast to the cytoskeleton, however, the nuclear matrix has been proposed to be a dynamic structure. Along with the nuclear lamina, it supposedly aids in organizing the genetic information within the cell.
Emerin is a protein that in humans is encoded by the EMD gene, also known as the STA gene. Emerin, together with LEMD3, is a LEM domain-containing integral protein of the inner nuclear membrane in vertebrates. Emerin is highly expressed in cardiac and skeletal muscle. In cardiac muscle, emerin localizes to adherens junctions within intercalated discs where it appears to function in mechanotransduction of cellular strain and in beta-catenin signaling. Mutations in emerin cause X-linked recessive Emery–Dreifuss muscular dystrophy, cardiac conduction abnormalities and dilated cardiomyopathy.
Lamina-associated polypeptide 2 (LAP2), isoforms beta/gamma is a protein that in humans is encoded by the TMPO gene. LAP2 is an inner nuclear membrane (INM) protein.
Laminopathies are a group of rare genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina. They are included in the more generic term nuclear envelopathies that was coined in 2000 for diseases associated with defects of the nuclear envelope. Since the first reports of laminopathies in the late 1990s, increased research efforts have started to uncover the vital role of nuclear envelope proteins in cell and tissue integrity in animals.
Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the LMNA gene. Lamin A/C belongs to the lamin family of proteins.
Lamin-B receptor is a protein, and in humans, it is encoded by the LBR gene.
LEM domain-containing protein 3 (LEMD3), also known as MAN1, is an integral protein in the inner nuclear membrane (INM) of the nuclear envelope. It is encoded by the LEMD3 gene and was first identified after it was isolated from the serum of a patient with a collagen vascular disease.
Chromobox protein homolog 3 is a protein that is encoded by the CBX3 gene in humans.
Nuclear pore glycoprotein-210 (gp210) is an essential trafficking regulator in the eukaryotic nuclear pore complex. Gp-210 anchors the pore complex to the nuclear membrane. and protein tagging reveals its primarily located on the luminal side of double layer membrane at the pore. A single polypeptide motif of gp210 is responsible for sorting to nuclear membrane, and indicate the carboxyl tail of the protein is oriented toward the cytoplasmic side of the membrane.
The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surrounds the nucleus, which encloses the genetic material.
Barrier-to-autointegration factor is a protein that in humans is encoded by the BANF1 gene. It is a member of the barrier-to-autointegration factor family of proteins.
Nesprin-2 is a protein that in humans is encoded by the SYNE2 gene. The human SYNE2 gene consists of 116 exons and encodes nesprin-2, a member of the nuclear envelope (NE) spectrin-repeat (nesprin) family. Nesprins are modular proteins with a central extended spectrin-repeat (SR) rod domain and a C-terminal Klarsicht/ANC-1/Syne homology (KASH) transmembrane domain, which acts as a NE-targeting motif. Nesprin-2 (Nesp2) binds to cytoplasmic F-actin, tethering the nucleus to the cytoskeleton and maintaining the structural integrity of the nucleus.
Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene. It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called HP1α. Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression. The C-terminal of this protein has a chromo shadow-domain (CSD) that is responsible for homodimerizing, as well as interacting with a variety of chromatin-associated, non-histone proteins.
Torsin-1A-interacting protein 1 is a protein that in humans is encoded by the TOR1AIP1 gene. More commonly known as lamina associated polypeptide 1 (LAP1), it is a type II integral membrane protein that resides in the inner nuclear membrane. The luminal domain of LAP1 interacts with Torsin A and is necessary for the ATPase activity of Torsin A. LAP1 plays a critical role in skeletal and heart muscle. Mutations in TOR1AIP1 have been linked to muscular dystrophy and cardiomyopathy. It's deletion from mouse hepatocytes leads to defected very-low density lipoprotein secretion and causes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis
Lamin-B1 is a protein that in humans is encoded by the LMNB1 gene.
Nuclear organization refers to the spatial distribution of chromatin within a cell nucleus. There are many different levels and scales of nuclear organisation. Chromatin is a higher order structure of DNA.