Lamina (nucleus)

The lamina contained in the eukaryotic cell nucleus is a dense, fibrillary bond, which lies largely directly under the nuclear envelope and is around 30 to 100 nm thick. It contains intermediate filaments and proteins that are connected to the inner membrane of the nuclear envelope. In addition to a supporting function, the lamina plays a role in processes such as the regulation of DNA replication and cell division as well as in chromatin organization.

Structure and structure

The lamina consists of lamines and lamin-binding membrane proteins. Lamines are the intermediate filaments of type V.

In the vertebrate genome, three lamin genes code for seven known lamin isoforms that are generated by alternative splicing . LMNA codes for the A-type lamines (A, AΔ10, C, and C2). The B-type lamines are encoded by two genes, lamin B1 from LMNB1 and lamines B2 and B3 from LMNB2 . Some lamines are specific for primordial germ cells and play an important role in the reorganization of chromatin during meiosis . Not all living things have the same number of genes coding for lamines; the fruit fly , for example, only has two genes, the nematode only one. Lamines are specific to animals . Plants or eukaryotic single cells such as baker's yeast have no lamines.

Lamines differ from cytoplasmic intermediate filaments by a longer amino acid sequence (42 more amino acids ). They carry a nuclear localization signal and form a typical tertiary structure . Lamin polypeptides have an almost complete α-helical shape with numerous α-helical protein domains , separated by non-α-helical linkages, which are invariable in length and amino acid sequence. Both the C-end and the N-end are non-α-helical, the C-end is globular . Their molecular weight ranges from 60 to 80 kilodaltons . A phosphorylation at the beginning of mitosis results in a conformational change that causes the breakdown 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 the Nesprine . Due to their position within or contact with the inner membrane, they cause the lamina to adhere to the nuclear envelope .

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Three-dimensional representation of a mouse cell nucleus from different angles recorded with 3D SIM microscopy . The cell is in an early stage of mitosis (prophase). The chromosomes (red) are already condensed. The surrounding lamina (green) shows prominent indentations and initial cracks.

Tasks and functions

The lamina is composed of two lamin polypeptides in which the alpha-helical regions wrap around each other to form a double-stranded alpha-helical spiral structure, followed by several dimers that extend over the entire length. The linearly elongated polymer is laterally expanded by opposing polymers, which results in a 2D structure that actually underlies the core membrane . In order to support the support function of the cell nucleus, the lamina plays an important role in chromatin organization, regulation of the cell cycle, DNA duplication, cell differentiation and in cell suicide .

Chromatin organization

The not accidental organization of the genome suggests that the lamina plays a role in the organization of chromatin . In fact, it has been found that lamin polypeptides have a tendency to bind chromatin through their alphahelical domains to specific DNA sequences called matrix appendage regions (MAR). 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 nuclear histones by means of a sequence in their end region.

Regulation of the cell cycle

At the beginning of mitosis ( prophase and prometaphase ), the cell is in the process of breaking down many cell structures, such as the nuclear membrane , the lamina, and the nuclear pores. This breakdown is necessary so that the spindle apparatus can come into contact with the (now spiraled) chromosomes and attach to their kinetochores .

These different degradation processes are triggered by cyclin proteins B and Cdk1. As soon as these are activated, the initiation of mitosis cannot be stopped, as further protein kinases have been activated and through the direct phosphorylation of structural proteins. After the phosphorylation by cyclin, the depolymerization of the lamina sets in and their B-lamines remain in contact with the pieces of the nuclear membrane, the A-lamines, however, are freely soluble in the cytoplasm during the entire mitosis . The importance of the dissolution of the lamina has been verified through experiments in which the lamina has been prevented from dissolving, which prevents all mitosis from occurring.

At the end of mitosis ( anaphase , telophase ) the rebuilding of the cell nucleus begins, which begins with the production of "skeletal" proteins on the surface of the still spiraling chromosomes, then the nuclear membrane is rebuilt. The new nuclear pores are formed, whereby the lamines carry the important nuclear localization signal and are therefore introduced. This characteristic hierarchy raises the question of whether the lamina assumes a stabilizing or regulating function at this point in time, although this does not play a major role in the creation of the membrane around the chromatin.

Embryo Development and Cell Differentiation

The presence of lamines during embryonic development has already been observed in organisms such as clawed frogs , chicks and mammals . Five different types have been identified in the clawed frog, which occur in the five different stages of embryonic development. The most common types are LI and LII, which are believed to be homologous to lamines B1 and B2. LA should be homologous to lamin A, LIII homologous to lamin B. A fourth type is germ cell-specific.

In the early embryonic development of a chick, only the B-lamines are present. In the following stages, the B1 content decreases, but more Lamin A occurs. Mammalian development appears to be similar. However, Lamin B is mainly available in the early stages. Lamin B1 reaches the highest concentration level in the early phases, whereby Lamin B2 is relatively constant there and the content only begins to increase after the cells have differentiated. After the various types of tissue have been developed at an advanced stage, the content of lamin A and C increases. These results suggest that the lamina only needs type B laminates in its basic structure.

Reduplication of the DNA

Numerous experiments show that the lamina plays a crucial role in DNA replication . Perhaps lamines create a scaffold that is important for assembling the extension complexes or they represent a starting point for assembling the backbone. Not only are lamines attached to the lamina present during the duplication, free lamina polypeptides also appear to be involved to have the process.

Apoptosis

Apoptosis (cell suicide) is a fundamental component of self-regulation and tissue , as it occurs when the cell degenerates or when viruses and other pathogens destroy the cell. This process is highly regulated and the lamina dissolves at an early stage.

In contrast to the dissolving of the lamina by phosphorylation during mitosis, the lamina is broken down by proteolysis and free as well as connected lamines are affected. This proteolysis is carried out by caspases , which split the lamines into aspartic acid .

Diseases

Gene defects that affect lamines (A and B1) can change them and thus trigger diseases. Examples are:

Emery Dreifuss muscular dystrophy - muscle breakdown
Progeria - premature aging

swell

Ayelet Margalit, Sylvia Vlcek, Yozef Gruenbaum, Roland Foisner (2005). Breaking and Making of the Nuclear Envelope. Journal of Cellular Biochemistry 95 , 454-465
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 , 533-547
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

Individual evidence

^ Goldman RD, Gruenbaum Y, Moir RD, Shumaker DK, Spann TP: Nuclear lamins: building blocks of nuclear architecture . In: Genes Dev. . 16, No. 5, March 2002, pp. 533-47. doi : 10.1101 / gad.960502 . PMID 11877373 .
↑ Libotte T, Zaim H, Abraham S, Padmakumar VC, Schneider M, Lu W, Munck M, Hutchison C, Wehnert M, Fahrenkrog B, Sauder U, Aebi U, Noegel AA, Karakesisoglou I: Lamin A / C-dependent localization of Nesprin-2, a giant scaffolder at the nuclear envelope . In: Mol Biol Cell. . 16, No. 7, April 2005, pp. 3411-3424. doi : 10.1091 / mbc.E04-11-1009 . PMID 15843432 . PMC 1165422 (free full text).

[pmid11877373-1] Goldman RD, Gruenbaum Y, Moir RD, Shumaker DK, Spann TP: Nuclear lamins: building blocks of nuclear architecture . In: Genes Dev. . 16, No. 5, March 2002, pp. 533-47. doi : 10.1101 / gad.960502 . PMID 11877373 .

[pmid15843432-2] Libotte T, Zaim H, Abraham S, Padmakumar VC, Schneider M, Lu W, Munck M, Hutchison C, Wehnert M, Fahrenkrog B, Sauder U, Aebi U, Noegel AA, Karakesisoglou I: Lamin A / C-dependent localization of Nesprin-2, a giant scaffolder at the nuclear envelope . In: Mol Biol Cell. . 16, No. 7, April 2005, pp. 3411-3424. doi : 10.1091 / mbc.E04-11-1009 . PMID 15843432 . PMC 1165422 (free full text).