Lamin

Lamins were first identified in the cell nucleus, using electron-microscopy. However, they were not recognized as vital components of nuclear structural support until 1975. During this time period, investigations of rat liver nuclei revealed that lamins have an architectural relationship with chromatin and nuclear pores. Later in 1978, immunolabeling techniques revealed that lamins are localized at the nuclear envelope under the inner nuclear membrane. It wasn't until 1986 that an analysis of lamin cDNA clones across a variety of species supported that lamins belong to the intermediate filament (IF) protein family. After this research, investigations of lamins slowed. Studies of lamins became more popular in the 1990s when it was discovered that mutations in the genes that code for lamins can be related to muscular dystrophies, cardiomyopathies, and neuropathies. Current research is being performed to develop treatment methods for the aforementioned laminopathies and to investigate the role lamins play in the aging process. == Structure ==

The structure of lamins is composed of three units that are common among intermediate filaments: a central α-helical rod domain containing heptad repeats surrounded by globular N and C-terminal domains. The N-terminal is shorter and located at the top (head) while the C-terminal is longer and located at the end (tail). Lamins have a unique structure of the heptad repeats that is continuous in nature and contains an additional six heptads. While the head domain of lamins is fairly consistent, the composition of the tail domain varies based on the type of lamin. However, all C-terminal domains contain a nuclear localization sequence (NLS). Similar to other IF proteins, lamins self-assemble into more complex structures. The basic unit of these structures is a coiled-coil dimer. The dimers arrange themselves in a head-to-tail manner, allowing for the formation of a protofilament. As these protofilaments aggregate, they form lamin filaments. Lamins of higher level organisms, such as vertebrates, continue to assemble into paracrystalline arrays. These complex structures allow nuclear lamins to perform their specialized functions in maintaining the shape of the nucleus as well as roles during mitosis and apoptosis. ==A- and B-types==

Lamins are divided into two major categories: A- and B-types. These subdivisions are based on similarities in cDNA sequences, structural features, isoelectric points, and expression trends. Two isoforms, lamins A and C, can be created from this gene via alternative splicing. This creates a high amount of homology between the isoforms. Some studies have demonstrated that lamins A and C are not required for the formation of the nuclear lamina, yet disruptions in the LMNA gene can contribute to physical and mental limitations. B-type lamins B-type lamins are characterized by an acidic isoelectric point, and they are typically expressed in every cell. As with A-type lamins, there are multiple isoforms of B-type lamins, the most common being lamin B1 and lamin B2. They are produced from two separate genes, LMNB1 and LMNB2. Similar to prelamin A, B-type lamins also contain a CaaX motif at the carboxyl-terminus. This marker triggers the same sequence of posttranslational modifications previously described for prelamin A except for the final cleavage step involving a zinc metalloprotease. Further investigations of B-type lamins across multiple species have found evidence that supports that B-type lamins existed before A-type lamins. This stems from the similarity in structure of B-type lamins between invertebrates and vertebrates. Furthermore, organisms that only contain a single lamin contain a B-type lamin. Other studies that have investigated the structural similarities and differences between A- and B-type lamins have found that the positions of introns/exons in B-type lamins have been conserved in A-type lamins, with more variations in the A-type lamins. This suggests that the common ancestor of these lamin types was a B-type lamin. ==Function==

Maintenance of nuclear shape Due to their properties as a type of IF protein, lamins provide support for maintaining the shape of the nucleus. They also play an indirect role in anchoring the nucleus to the endoplasmic reticulum, forming a continuous unit within the cell. This is accomplished by lamin and lamin-interacting proteins (SUN1/SUN2) connecting with proteins on the outer nuclear membrane. These proteins in turn interact with cytoskeletal elements of the endoplasmic reticulum, forming a strong complex that can withstand mechanical stress. Nuclei that lack lamins or have mutated versions have a deformed shape and do not function properly. Mitosis During mitosis, lamins are phosphorylated by the mitosis-promoting factor (MPF), which drives the disassembly of the lamina and the nuclear envelope. This allows chromatin to condense and the DNA to be replicated. After chromosome segregation, dephosphorylation of nuclear lamins by a phosphatase promotes reassembly of the nuclear envelope. Apoptosis Apoptosis is a highly organized process of programmed cell death. Lamins are crucial targets for this process due to their close associations with chromatin and the nuclear envelope. Apoptotic enzymes called caspases target lamins and cleave both A- and B-types. This allows chromatin to separate from the nuclear lamina in order to be condensed. As apoptosis continues, cell structures slowly shrink into compartmentalized "blebs." Finally, these apoptotic bodies are digested by phagocytes. Studies of apoptosis involving mutant A- and B-type lamins that are resistant to cleavage by caspases show decreased DNA condensation and apoptotic "blebbing" formation, thereby underscoring the important role of lamins in apoptosis. == Clinical significance ==

Mutations in the LMNA gene, encoding Lamins A and C, can produce a series of disorders ranging from muscular dystrophies, neuropathies, cardiomyopathies, and premature ageing syndromes. Collectively, these conditions are known as laminopathies. Hutchinson-Gilford progeria syndrome One specific laminopathy is Hutchinson-Gilford progeria syndrome (HGPS), characterized by premature ageing. Those affected by the condition appear normal at birth, but show signs of premature ageing including hair-loss, thinness, joint abnormalities, and weak motor skills as they develop. Furthermore, health problems usually seen in older persons such as atherosclerosis and high blood pressure occur at a much younger age. Those with HGPS typically die in their early teens, usually following a heart attack or stroke. HGPS is caused by a point mutation in the LMNA gene that codes for lamin A. The genetic alteration results in an alternative splice, creating a mutated form of prelamin A that is much shorter and lacks the cleavage site for a zinc metalloprotease. Because prelamin A cannot be properly processed during posttranslational modifications, it retains its lipid modification (farnesylation) and remains in the inner nuclear membrane. This disrupts the mechanical stability of the nucleus, resulting in a higher rate of cell death and therefore a higher rate of aging. ==References==