Lamin
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.[1] Lamins are present in all animals but are not found in microorganisms, plants or fungi.[2][3] 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.
History
Lamins were first identified in the cell nucleus, using
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).[2][10] Lamins have a unique structure of the heptad repeats that is continuous in nature and contains an additional six heptads.[11] 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.[2] 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.[2][5]
A-type lamins
A-type lamins are characterized by a neutral
B-type lamins
B-type lamins are characterized by an acidic isoelectric point, and they are typically expressed in every cell.[12][15] 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.[9] 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.[9][13] 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.[6] 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.[6] Nuclei that lack lamins or have mutated versions have a deformed shape and do not function properly.[2]
Mitosis
During mitosis, lamins are phosphorylated by 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.[15] 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.[3] 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.[10]
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.[3][16]
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.[3] Current studies are investigating the effects of farnesyl-transferase inhibitors (FTIs) to see if farnesyl attachment can be inhibited during posttranslational modification of prelamin A in order to treat patients with HGPS.[8]
Lamin A/C heart disease
Some laminopathies affect
References
- PMID 27754432.
- ^ PMID 20826548.
- ^ ISBN 9780321934925.
- ^ PMID 10806083.
- ^ PMID 19587451.
- ^ PMID 21639948.
- ^ Cooper, Geoffrey M. (2000-01-01). "Intermediate Filaments". The Cell: A Molecular Approach. 2nd Edition.
- ^ a b Simpkins, Beth. "A Comeback for the Ages: Lamin's connection with aging has reinvigorated research". Retrieved 2016-11-24.
- ^ PMID 24842906.
- ^ PMID 18381888.
- PMID 11877373.
- ^ PMID 9724605.
- ^ PMID 19154754.
- PMID 11331313.
- ^ PMID 10806082.
- ^ Reference, Genetics Home. "Hutchinson-Gilford progeria syndrome". Genetics Home Reference. Retrieved 2016-11-24.
- S2CID 3563474.
External links
- Lamins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)