Lamins: Organisation, Dynamics and Functions

Abstract

Lamins are evolutionary conserved nuclear intermediate filaments. They are the major component of a protein network, termed the nuclear lamina, which is located underneath the inner nuclear membrane of the nuclear envelope. A small fraction of lamins also localise throughout the nucleoplasm. Lamins are involved in most nuclear functions including mechanical stability, cytoskeletal organisation, genome stability, chromatin organisation, differentiation and tissue‐specific functions. During the past two decades, interest in lamins increased due to the discovery of over 450 missense mutations in the human LMNA gene causing more than 15 different heritable diseases. These disorders are collectively known as nuclear envelopathies or laminopathies and range from muscular dystrophies to accelerated ageing disorders, affecting a range of different tissue types. Understanding lamins' structure, dynamics and functions is key in elucidating the elusive molecular mechanisms leading to these disorders.

Key Concepts

  • The nuclear envelope separates the nucleus from the cytoplasm and is composed of an outer nuclear membrane, an inner nuclear membrane, nuclear pore complexes and nuclear lamina.
  • Lamins are the main components of the nuclear lamina.
  • Unique features of lamins include a nuclear localisation signal (NLS), an immunoglobulin fold and a carboxyl tail CaaX (C = cysteine, a = aliphatic amino acid, X = any amino acid) motif.
  • Lamins are grouped into A‐ and B‐type lamins based on their biochemical properties and behaviour during mitosis.
  • Each metazoan cell expresses at least one B‐type lamin.
  • Lamins are involved in most nuclear functions.
  • In mammals, the A‐ to B‐type lamin ratio regulates the differentiation state of cells.
  • Mutations in lamins can have dramatic effects on their higher order structures.
  • Lamins interact with a plethora of proteins in the nuclear membrane and nucleoplasm.
  • Mutations in human lamin genes, and especially the LMNA gene, cause over 15 distinct diseases effecting different tissues.

Keywords: intermediate filaments; nuclear lamina; nuclear envelope; laminopathies; lamin dynamics; lamin assembly; lamin structure

Figure 1. Schematic view of the nuclear envelope, lamina and chromatin. The inner nuclear membrane (INM) and the outer nuclear membranes (ONM) are joined at the NPCs and are separated by the nuclear lumen. The ONM and lumen are continuous with the endoplasmic reticulum (ER). Lamins (both A‐ and B‐types) are shown as orange filaments. They are thicker at the nuclear periphery and thinner in the nucleoplasm. However, the filamentous nature of the lamins, especially within the nucleus, remains hypothetical. Also shown are selected proteins of the INM including LEM domain and SUN domain proteins, LAP‐1, Nurim and LBR (boudreaux). These proteins represent only a small fraction of proteins of the INM. Also shown are a few examples of non‐integral proteins that interact with lamins or with their associated proteins including actin, HP1, HA95, germ cell‐less and BAF. The nucleoplasmic lamins also form specific protein complexes (not shown). INM SUN‐domain proteins interact with outer nuclear membrane (ONM) KASH‐domain proteins, thus bridging between the nucleus and the cytoplasm.
Figure 2. Lamin assembly and defects caused by lamin mutations. Two parallel lamin monomers (a) form dimers (b) through coiled‐coil interaction of the heptad repeats in their central rod domains. In vitro, the lamin dimers assemble head‐to‐tail by overlapping their rod domains to form a polymer of lamin dimers. The head‐to‐tail polymers form non‐polar protofilaments composed of two anti‐parallel polymers with specific repeat units. Three to four protofilaments can laterally assemble to form mature 10‐nm‐wide lamin filaments. Defects in lamin assembly can be identified in vitro by changes in the spacing of the repeat unit, as demonstrated by two mutants in C. elegans (c) or by failure to form lamin filaments. Note that, in the case of the Q159K mutation, it is likely that the spacing is 17/17/17, approximately corresponding to the 48 nm repeat unit, indicating a combination of three overlapping polymers instead of two. (b) Inset: a cross‐sectional view of the heptad repeats of the coiled coil illustrates how the inner amino acids play a role in dimer assembly, whereas amino acids that point outwards can affect higher order assembly. The protofilaments are also the basic assembly units ex vivo (and also probably in vivo), as 10‐nm‐wide filaments are not observed in somatic cells. Reproduced with permission from Davidson PM, Lammerding J 2014 © Cell Press.
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Further Reading

Burke B and Stewart CL (2013) The nuclear lamins: flexibility in function. Nat. Rev. Mol. Cell. Biol. 14 (1): 13–24.

Butin‐Israeli V , Adam SA , Goldman AE and Goldman RD (2012) Nuclear lamin functions and disease. Trende Genet 28 (9): 464–471.

Gruenbaum Y and Medalia O (2014) Lamins: the structure and protein complexes. Current Opinion in Cell Biology 32: 7–12.

Schreiber KH and Kennedy BK (2013) When lamins go bad: nuclear structure and disease. Cell 152: 1365–1375.

Lammerding J (2011) Mechanics of the nucleus. Compr. Physiol. 1 (2): 783–807.

Worman HJ and Bonne G (2007) “Laminopathies”: a wide spectrum of human diseases. Exp Cell Res 313 (10): 2121–2133.

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Zuela, Noam, and Gruenbaum, Yosef(Feb 2015) Lamins: Organisation, Dynamics and Functions. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001342.pub3]