Nuclear lamina

The included eukaryotic nuclear lamina is a dense, fibrillar network, which is largely just beneath the nuclear envelope and is about 30 to 100 nm thick. It comprises intermediate filaments, and proteins associated with the inner membrane of the nuclear envelope. In addition to a support function, the lamina has a role in processes such as the regulation of DNA replication and cell division, as well as chromatin.

• 4.1 Notes and references

Structure and organization

The lamina consists of lamins and lamin -binding membrane proteins. Lamine are the intermediate filaments of type 5

In the genome of vertebrates encode three lamin genes for seven known lamin isoforms generated by alternative splicing. LMNA coding for the A- type lamins (A, AΔ10, C, and C2). The B-type lamins are encoded by two genes, Lamin B1 of LMNB1 and lamins B2 and B3 from LMNB2. Some Lamine specific to primordial germ cells and play an important role in the reorganization of chromatin during meiosis. Not all organisms have the same number coding to lamins genes, fruit flies have, for example, only two genes, the nematode only one. Lamine are specific to animals. Plants or unicellular eukaryotic yeast do not like Lamine.

Lamine differ from cytoplasmic intermediate filaments by a longer amino acid sequence ( 42 amino acids longer ). They carry a nuclear localization signal and form a typical tertiary structure. Lamin polypeptides have an almost complete α -helical configuration with numerous α -helical protein domains separated by non- α -helical threads, which are fixed in length and amino acid sequence. Both the C-terminus and the N-terminus are non- α -helical, the C-terminus is globular. Their molecular weight ranges from 60 to 80 kilodaltons. Phosphorylation at the beginning of mitosis leading to a conformational change that causes the degradation of the lamina.

Lamin -binding membrane proteins are either integral or peripheral. The most important are LAP1 and LAP2 ( for lamin associated protein ), emerin, lamin B receptor (LBR ), Otefin, MAN1 and Nesprins. Because of their position within the inner membrane or her contact with this, they bring about the adhesion of the lamina to the nuclear envelope.

Tasks and functions

The lamina is composed of two lamin polypeptides in which the alpha- Helikalregionen wind around each other to form a double-stranded alphahelikale spiral structure, after which follow several dimers, which extend over the entire length. The linearly extended polymer is laterally extended by opposing polymers, resulting in a 2D structure, which is actually based on the nuclear membrane. To assist in the supporting function of the nucleus, the lamina plays an important role in chromatin organization, regulation of the cell cycle, DNA duplication, and Zellausdifferenzierung in cell suicide.

Chromatin

The non-random organization of the genome suggests here that the lamina has a role in the organization of the chromatin. In fact, it was found that lamin polypeptides have a propensity to carry their alpha helical domains to specific DNA binding chromatin sequences extending matrix attachments regions ( MAR) call. A MAR has an average length of 300-1000 base pairs and has a particularly high adenine / thymine content. Lamin A and B can also bind core histones by means of a sequence in its end region.

Regulation of the cell cycle

At the beginning of mitosis ( prophase and prometaphase ) the cell is to reduce many cellular structures, such as the nuclear membrane, the lamina, and the core pores. This reduction is necessary so that the spindle apparatus with the (now spiraled ) chromosomes can come into contact and to attach to their centromeres.

These different degradation processes are triggered by cyclin proteins B and Cdk1. Once they are activated, the initiation of mitosis is unstoppable, as more protein kinases were activated and through the direct phosphorylation of structural proteins. After phosphorylation by cyclin the depolymerization of the lamina and which is a B- lamins remain in contact with the pieces of the nuclear membrane, the A, however, are free lamins throughout mitosis soluble in the cytoplasm. The importance of the resolution of the lamina was verified by experiments in which one has the lamina prevented the resolution, which the entire mitosis can not take place.

At the end of mitosis ( anaphase, telophase ) of reconstruction of the nucleus, the proteins with the generation of "skeleton" begins starts from the surface of the still spiral- chromosomes, and then the core of the membrane is restored. The new nuclear pores are formed, the Lamine carry the major nuclear localization signal and are therefore introduced. This characteristic hierarchy raises the question whether at this time the lamina a Stabilierungsfunktion or a regulatory function takes, which plays no major role in the membrane preparation to the chromatin around.

Embryo development and cell differentiation

The presence of lamins in embryonic development has already been observed in organisms as clawed frogs, chicks or mammals. The clawed frog five different types have been identified that appear at the five different stages of embryonic development. The most common types LI and LII are found, of which one assumes that they are homologous to the lamins B1 and B2. LA should be homologous to Lamin A, Lamin LIII homologous to B. A fourth type is germ cell specific.

In the early embryo of a chick, only the B- lamins are present. In the subsequent stages of the B1 content decreases, it is more important lamin A before. The development in mammals seems similar expire. Here, however, lamin B is present mainly in the early stages. Lamin B1 reaches the highest concentration level in the early stages, with lamin B2 there is relatively constant and the content begins to increase only after cell differentiation. After the development of the various tissue types in an advanced stage, the content of lamin A and C. This increase results suggest that the basic structure of the lamina only Lamine required type B.

Reduplication of DNA

Numerous experiments demonstrate that the lamina plays a crucial role in DNA replication. Maybe Lamine produce a scaffold that is important for the assembly of the extension complexes or they provide a starting point for the assembly of the backbone dar. Not only lamins, which are connected with the lamina, are present during doubling, even free Laminpolypeptide seem a assisting in to have the process.

Apoptosis

Apoptosis (cell suicide ) is a fundamental component of self-regulation and the tissue, as it occurs with degeneration of the cell or when viruses and other pathogens destroying the cell. This process is highly regulated, the lamina solubilisation in an early stage.

In contrast to the dissolution of the lamina by phosphorylation during mitosis in this case the lamina is degraded by proteolysis and it is free as associated Lamine affected. This proteolysis is carried out by caspases, which cleave lamins by aspartic acid.

Diseases

Genetic defects that affect lamins (A and B1) can change this and cause such diseases. Examples are:

• Progeria - Premature aging

Swell

• Bruce Alberts, et al. Molecular Biology of the Cell (4th edition). Garland Science 676-677
• Geoffrey M. Cooper, Robert E. Hausman. The Cell, A Molecular Approach ( 4th edition). Sinauer Associates 356-360
• Goldman et al. (2002). " Nuclear lamins: building blocks of nuclear architecture". Genes and Development 16.533 to 547
• Joanna M. Bridger, Nicole Foeger, Ian R. Kill, Harald Herrmann ( 2007). The Nuclear Lamina: both a structural framework and a platform for genome organization. FEBS Journal 274, 1354-1361
• Nico Stuurman, Susanne Heins, Ueli Aebi (1998). Nuclear lamins: Their Structure, Assembly and Interactions. Journal of Structural Biology 122, 42-46
• Yozef Gruenbaum, Katherine L. Wilson, Amnon Harel, Michal Goldberg, Merav Cohen ( 2000). Nuclear lamins - structural proteins with fundamental functions. Journal of Structural Biology 129, 313-323