Lamins: Organisation, Dynamics and Functions

Abstract

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.