Nuclear lamina
Encyclopedia
The nuclear lamina is a dense (~30 to 100 nm thick) fibrillar network inside the nucleus
of a eukaryotic cell
. It is composed of intermediate filament
s 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.
The nuclear lamina is associated with the inner face of the bilayer nuclear envelope
whereas the outer face stays continuous with the endoplasmic reticulum
.
(NLS) at their C-terminus and that they display typical tertiary structure
s. Lamin polypeptides have an almost complete α-helical conformation with multiple α-helical domains separated by non-α-helical linkers that are highly conserved in length and amino acid
sequence. Both the C-terminus and the N- terminus are non α-helical, with the C-terminus displaying a globular structure. Their molecular weight ranges from 60 to 80 kilodaltons (kDa).
In the amino acid sequence of nuclear lamins, there are also two phosphoacceptor sites present, flanking the central rod domain. A phosphorylation
event at the onset of mitosis
leads to a conformational change which causes the disassembly of the nuclear lamina. (discussed later in the article)
In the vertebrate
genome, lamins are encoded by three genes. By alternative splicing
, at least seven different polypeptides (splice variants) are obtained, some of which are specific for germ cell
s and play an important role in the chromatin reorganisation during meiosis
. Not all organisms have the same number of lamin encoding genes; Drosophila melanogaster
for example has only 2 genes, whereas Caenorhabditis elegans
has only one.
The presence of lamin polypeptides is an exclusive property of Metazoan organisms. Plants or single-cell Eukaryotic organisms such as Saccharomyces cerevisiae
lack lamins.
The nuclear lamin-associated membrane proteins are either integral or peripheral membrane proteins. The most important are lamin associated polypeptide 1 and 2 (LAP1, LAP2
), emerin, lamin B-receptor (LBR), otefin and MAN1. Due to their positioning within or their association with the inner membrane, they mediate the attachment of the nuclear lamina to the nuclear envelope.
s. The linearly elongated polymer is extended laterally by a side-by-side association of polymers, resulting in a 2D structure underlying the nuclear envelope. Next to providing mechanical support to the nucleus, the nuclear lamina plays an essential role in chromatin organization, cell cycle regulation, DNA replication, cell differentiation and apoptosis.
, prometaphase
) the cellular machinery is engaged in the disassembly of various cellular components including structures such as the nuclear envelope, the nuclear lamina and the nuclear pore complexes. This nuclear breakdown is necessary to allow the mitotic spindle
to interact with the (condensed) chromosomes and to bind them at their kinetochores.
These different disassembly events are initiated by the cyclin B
/Cdk1
protein kinase complex (MPF
). Once this complex is activated, the cell is forced into mitosis, by the subsequent activation and regulation of other protein kinase
s or by direct phosphorylation of structural proteins involved in this cellular reorganisation. After phosphorylation by cyclin B/Cdk1, the nuclear lamina depolymerises and B-type lamins stay associated with the fragments of the nuclear envelope whereas A-type lamins remain completely soluble throughout the remaining of the mitotic phase.
The importance of the nuclear lamina breakdown at this stage is underlined by experiments where inhibition of the disassembly event leads to a complete cell cycle arrest.
At the end of mitosis, (anaphase
, telophase
) there is a nuclear reassembly which is highly regulated in time, starting with the association of 'skeletal' proteins on the surface of the still partially condensed chromosomes, followed by nuclear envelope assembly. Novel nuclear pore complexes are formed through which nuclear lamins are actively imported by use of their NLS. This typical hierarchy raises the question whether the nuclear lamina at this stage has a stabilizing role or some regulative function, for it is clear that it plays no essential part in the nuclear membrane assembly around chromatin.
laevis, the chick and mammals. In Xenopus laevis, five different types were identified which are present in different expression patterns during the different stages of the embryonic development. The major types are LI and LII, which are considered homologs of lamin B1 and B2. LA are considered homologous to lamin A and LIII as a B-type lamin. A fourth type exists and is germ cell specific.
In the early embryonic stages of the chick, the only lamins present are B-type lamins. In further stages, the expression pattern of lamin B1 decreases and there is a gradual increase in the expression of lamin A. Mammalian development seems to progress in a similar way. In the latter case as well it is the B-type lamins that are expressed in the early stages. Lamin B1 reaches the highest expression level, whereas the expression of B2 is relatively constant in the early stages and starts to increase after cell differentiation. With the development of the different kinds of tissue in a relatively advanced developmental stage, there is an increase in the levels of lamin A and lamin C.
These findings would indicate that in its most basic form, a functional nuclear lamina requires only B-type lamins.
phase of DNA replication. It has been suggested that lamins provide a scaffold, essential for the assembly of the elongation complexes, or that it provides an initiation point for the assembly of this nuclear scaffold.
Not only nuclear lamina associated lamins are present during replication, but free lamin polypeptides are present as well and seem to have some regulative part in the replication process.
of tissue and in defending the organism against invasive entry of viruses or other pathogens. Apoptosis is a highly regulated process in which the nuclear lamina is disassembled in an early stage.
In contrast to the phosphorylation-induced disassembly during mitosis, the nuclear lamina is degraded by proteolytic cleavage, and both the lamins and the nuclear lamin-associated membrane proteins are targeted. This proteolytic activity is performed by members of the caspase
-protein family who cleave the lamins after aspartic acid
(Asp) residues.
) such as:
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of a eukaryotic cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. It is composed of intermediate filament
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
s and membrane associated proteins. Besides providing mechanical support, the nuclear lamina regulates important cellular events such as DNA replication and cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
. Additionally, it participates in chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
organization and it anchors the nuclear pore complexes embedded in the nuclear envelope.
The nuclear lamina is associated with the inner face of the bilayer nuclear envelope
Nuclear envelope
A nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...
whereas the outer face stays continuous with the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
.
Structure and composition
The nuclear lamina consists of two components, lamins and nuclear lamin-associated membrane proteins. The lamins are type V intermediate filaments which can be categorized as either A-type (lamin A, C) or B-type(lamin B1, B2) according to homology in sequence, biochemical properties and cellular localization during the cell cycle. Type V intermediate filaments differ from cytoplasmic intermediate filaments in the way that they have an extended rod domain (42 amino acid longer), that they all carry a nuclear localization signalNuclear localization signal
A nuclear localization signal or sequence is an amino acid sequence which 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different...
(NLS) at their C-terminus and that they display typical tertiary structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
s. Lamin polypeptides have an almost complete α-helical conformation with multiple α-helical domains separated by non-α-helical linkers that are highly conserved in length and amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence. Both the C-terminus and the N- terminus are non α-helical, with the C-terminus displaying a globular structure. Their molecular weight ranges from 60 to 80 kilodaltons (kDa).
In the amino acid sequence of nuclear lamins, there are also two phosphoacceptor sites present, flanking the central rod domain. A phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
event at the onset of mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
leads to a conformational change which causes the disassembly of the nuclear lamina. (discussed later in the article)
In the vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
genome, lamins are encoded by three genes. By alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
, at least seven different polypeptides (splice variants) are obtained, some of which are specific for germ cell
Germ cell
A germ cell is any biological cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate near the gut of an embryo and migrate to the developing gonads. There, they undergo cell division of two types, mitosis and meiosis, followed by...
s and play an important role in the chromatin reorganisation during meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
. Not all organisms have the same number of lamin encoding genes; Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
for example has only 2 genes, whereas Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
has only one.
The presence of lamin polypeptides is an exclusive property of Metazoan organisms. Plants or single-cell Eukaryotic organisms such as Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
lack lamins.
The nuclear lamin-associated membrane proteins are either integral or peripheral membrane proteins. The most important are lamin associated polypeptide 1 and 2 (LAP1, LAP2
Thymopoietin
Lamina-associated polypeptide 2, isoforms beta/gamma is a protein that in humans is encoded by the TMPO gene.Thymopoietin is a protein involved in the induction of CD90 in the thymus. The thymopoetin gene encodes three alternatively spliced mRNAs encoding proteins of 75 kDa , 51 kDa and 39 kDa ...
), emerin, lamin B-receptor (LBR), otefin and MAN1. Due to their positioning within or their association with the inner membrane, they mediate the attachment of the nuclear lamina to the nuclear envelope.
Role and interaction aspects
The nuclear lamina is assembled by interactions of two lamin polypeptides in which the α-helical regions are wound around each other to form a two stranded α-helical coiled-coil structure, followed by a head-to-tail association of the multiple dimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
s. The linearly elongated polymer is extended laterally by a side-by-side association of polymers, resulting in a 2D structure underlying the nuclear envelope. Next to providing mechanical support to the nucleus, the nuclear lamina plays an essential role in chromatin organization, cell cycle regulation, DNA replication, cell differentiation and apoptosis.
Chromatin organization
The non-random organization of the genome strongly suggests that the nuclear lamina plays a role in chromatin organization. Indeed, it has been shown that lamin polypeptides have an affinity for binding chromatin through their α-helical (rod like) domains at specific DNA sequences called matrix attachment regions (MAR). A MAR has a length of approximately 300–1000 bp and has a high A/T content. Lamin A and B can also bind core histones through a sequence element in their tail domain.Cell cycle regulation
At the onset of mitosis, (prophaseProphase
Prophase, from the ancient Greek πρό and φάσις , is a stage of mitosis in which the chromatin condenses into a highly ordered structure called a chromosome in which the chromatin becomes visible. This process, called chromatin condensation, is mediated by the condensin complex...
, prometaphase
Prometaphase
Prometaphase is the phase of mitosis following prophase and preceding metaphase, in eukaryotic somatic cells. In Prometaphase, The nuclear envelope breaks into fragments and disappears. The tiny nucleolus inside the nuclear envolope, also dissolves. Microtubules emerging from the centrosomes at the...
) the cellular machinery is engaged in the disassembly of various cellular components including structures such as the nuclear envelope, the nuclear lamina and the nuclear pore complexes. This nuclear breakdown is necessary to allow the mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
to interact with the (condensed) chromosomes and to bind them at their kinetochores.
These different disassembly events are initiated by the cyclin B
Cyclin B
Cyclin B is a member of the cyclin family.Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B...
/Cdk1
Cdk1
Cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S....
protein kinase complex (MPF
MPF
MPF may refer to:* Malta Police Force, the national police force of the Republic of Malta* Mauritius Police Force, the national police force of the Republic of Mauritius* Managed Package Framework, Microsoft technology...
). Once this complex is activated, the cell is forced into mitosis, by the subsequent activation and regulation of other protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s or by direct phosphorylation of structural proteins involved in this cellular reorganisation. After phosphorylation by cyclin B/Cdk1, the nuclear lamina depolymerises and B-type lamins stay associated with the fragments of the nuclear envelope whereas A-type lamins remain completely soluble throughout the remaining of the mitotic phase.
The importance of the nuclear lamina breakdown at this stage is underlined by experiments where inhibition of the disassembly event leads to a complete cell cycle arrest.
At the end of mitosis, (anaphase
Anaphase
Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....
, telophase
Telophase
Telophase from the ancient Greek "τελος" and "φασις" , is a stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase events are reversed. Two daughter nuclei form in the cell. The nuclear envelopes of the daughter cells are formed from the...
) there is a nuclear reassembly which is highly regulated in time, starting with the association of 'skeletal' proteins on the surface of the still partially condensed chromosomes, followed by nuclear envelope assembly. Novel nuclear pore complexes are formed through which nuclear lamins are actively imported by use of their NLS. This typical hierarchy raises the question whether the nuclear lamina at this stage has a stabilizing role or some regulative function, for it is clear that it plays no essential part in the nuclear membrane assembly around chromatin.
Embryonic development and cell differentiation
The presence of lamins in embryonic development is readily observed in various model organisms such as XenopusXenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
laevis, the chick and mammals. In Xenopus laevis, five different types were identified which are present in different expression patterns during the different stages of the embryonic development. The major types are LI and LII, which are considered homologs of lamin B1 and B2. LA are considered homologous to lamin A and LIII as a B-type lamin. A fourth type exists and is germ cell specific.
In the early embryonic stages of the chick, the only lamins present are B-type lamins. In further stages, the expression pattern of lamin B1 decreases and there is a gradual increase in the expression of lamin A. Mammalian development seems to progress in a similar way. In the latter case as well it is the B-type lamins that are expressed in the early stages. Lamin B1 reaches the highest expression level, whereas the expression of B2 is relatively constant in the early stages and starts to increase after cell differentiation. With the development of the different kinds of tissue in a relatively advanced developmental stage, there is an increase in the levels of lamin A and lamin C.
These findings would indicate that in its most basic form, a functional nuclear lamina requires only B-type lamins.
DNA replication
Various experiments show that the nuclear lamina plays a part in the elongationElongation
In astronomy, a planet's elongation is the angle between the Sun and the planet, as viewed from Earth. Elongations occur when an inner planet’s position, in its orbital path, is at tangent to the view from Earth. Because these inner planets are inside the Earth’s orbits their positions as viewed...
phase of DNA replication. It has been suggested that lamins provide a scaffold, essential for the assembly of the elongation complexes, or that it provides an initiation point for the assembly of this nuclear scaffold.
Not only nuclear lamina associated lamins are present during replication, but free lamin polypeptides are present as well and seem to have some regulative part in the replication process.
Apoptosis
Apoptosis, basically to be considered as cellular suicide is of the highest importance in homeostasisHomeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
of tissue and in defending the organism against invasive entry of viruses or other pathogens. Apoptosis is a highly regulated process in which the nuclear lamina is disassembled in an early stage.
In contrast to the phosphorylation-induced disassembly during mitosis, the nuclear lamina is degraded by proteolytic cleavage, and both the lamins and the nuclear lamin-associated membrane proteins are targeted. This proteolytic activity is performed by members of the caspase
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
-protein family who cleave the lamins after aspartic acid
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
(Asp) residues.
Laminopathies
Defects in the genes encoding for nuclear lamin (such as lamin A and lamin B1) have been implicated in a variety of diseases (laminopathiesLaminopathy
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...
) such as:
- Emery-Dreifuss muscular dystrophyEmery-Dreifuss muscular dystrophyEmery–Dreifuss muscular dystrophy is a condition that chiefly affects muscles used for movement and heart muscle.It is named after Alan Eglin H. Emery and Fritz E. Dreifuss.-Presentation:...
- A muscle wasting disease - ProgeriaProgeriaProgeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
- Premature aging - Restrictive dermopathyRestrictive dermopathyRestrictive dermopathy is a rare, lethal autosomal recessive skin condition characterized by abnormal facies, tight skin, sparse or absent eyelashes, and secondary joint changes.- Mechanism :...
- A disease associated with extremely tight skin and other severe neonatal abnormalities