Trends in Cell Biology
Volume 28, Issue 1, January 2018, Pages 34-45
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Review
Nuclear Lamins: Thin Filaments with Major Functions

https://doi.org/10.1016/j.tcb.2017.08.004Get rights and content

Trends

Lamins are nuclear IFs that make a meshwork of filaments at the nuclear periphery. Each major lamin isoform forms a separate meshwork.

The lamin filaments are organized in somatic cells as protofilaments with a diameter of 3.5 nm in mammalian cells and 4–6 nm in C. elegans.

Mutations in lamin A and B1 cause numerous laminopathies affecting muscle, adipose, nerve, bone, and skin, and can also cause early-aging diseases. These mutations can modify lamin filament organization and nuclear mechanical properties.

Lamin filament organization in vitro is different from that observed in vivo, which is probably due to lamin-binding proteins and lamin post-translational modifications.

Lamin-binding proteins are also involved in mediating lamin functions such as signaling, cell-cycle regulation, and chromatin organization.

The nuclear lamina is a nuclear peripheral meshwork that is mainly composed of nuclear lamins, although a small fraction of lamins also localizes throughout the nucleoplasm. Lamins are classified as type V intermediate filament (IF) proteins. Mutations in lamin genes cause at least 15 distinct human diseases, collectively termed laminopathies, including muscle, metabolic, and neuronal diseases, and can cause accelerated aging. Most of these mutations are in the LMNA gene encoding A-type lamins. A growing number of nuclear proteins are known to bind lamins and are implicated in both nuclear and cytoskeletal organization, mechanical stability, chromatin organization, signaling, gene regulation, genome stability, and cell differentiation. Recent studies reveal the organization of the lamin filament meshwork in somatic cells where they assemble as tetramers in cross-section of the filaments.

Introduction

The nuclear lamina is a protein structure at the nuclear periphery which provides structural support to the nucleus and helps to protect the chromatin [1] (Figure 1, Key Figure). Lamins, the major constituent of the nuclear lamina, form a dense meshwork of filaments which interact with a large number of binding partners. Together with their binding partners, lamins form the nuclear lamina. In addition to maintaining the structural integrity of the nucleus, lamins are involved in several other cellular functions such as chromatin organization, DNA repair, and nuclear assembly/disassembly [2]. How lamins regulate a wide range of structural and cellular processes is presently unclear.

Based on their sequence, lamins are classified into a separate intermediate filament (IF; see Glossary) group (type V). Other IF groups include keratins (types I and II), desmin and vimentin (type III), and neurofilaments (type IV), which are all found in the cytoplasm of multicellular organisms [3]. In mammalian cells, the nuclear lamina is composed of predominantly four lamin isoforms, namely two A-type lamins (A and C) and two B-type lamins (B1 and B2). The LMNA gene encodes the A-type lamins, whereas LMNB1 and LMNB2 genes encode lamins B1 and B2, respectively. Lamins share similar protein domains with other IF proteins [4]. They consist of an N-terminal head domain, a coiled-coil central rod domain, and a C-terminal tail domain. Their unique features are a nuclear localization signal (NLS), an immunoglobulin (Ig)-fold domain, and a CaaX motif (C, cysteine; a, aliphatic residue; X, any residue) at the tail domain [4]. Interestingly, a small fraction mainly of the more soluble A-type lamins are found in the nucleoplasm [5]. However, the assembly states of these fractions are not known [6].

Lamins undergo several post-translational modifications (PTMs). For example, lamins A, B1, and B2 have the C-terminal CaaX motif in which the cysteine is post-translationally modified by farnesylation and methyl esterification. However, mature lamin A undergoes further proteolytic cleavage which removes the modified C-terminal cysteine together with an additional 14 amino acids. Therefore, only B-type lamins remain permanently farnesylated. One known exception is the Caenorhabditis elegans lamin (Ce-lamin), encoded by a single lamin gene (LMN-1), which displays known characteristics of A-type lamins, such as maintaining nuclear shape and interactions with recognized binding partners, but remains farnesylated. Furthermore, lamin proteins can undergo other PTMs including phosphorylation [7], SUMOylation [8], and glycosylation [9] (Box 1).

Mutations in LMNA are associated with a variety of diseases, named laminopathies (Box 2). To date, over 600 disease-causing mutations have been mapped to the LMNA gene. Laminopathies include diseases affecting striated muscle, lipodystrophies, peripheral neuropathy, and accelerated aging disorders, of which Hutchinson–Gilford progeria syndrome is arguably the best-studied [10]. Many of the mutations are autosomal dominant, and laminopathies are rare diseases. To understand how a mutation in the lamin meshwork can have such detrimental effects, and how mutations can lead to diseases which affect many different tissues, it is important to understand how the lamin meshwork is organized in healthy tissues and is altered in disease states in different cell types. The structure of the nuclear lamina has long remained elusive. Recent advances have given new insights into the structural organization of the lamin meshwork within the nuclear lamina.

In this review we discuss the current knowledge on the structure of lamins and the nuclear lamina, as well as their biological functions and why mutations in these proteins cause so many diseases.

Section snippets

Structural Determination of Lamin Subdomains

It is a challenging task to determine the structure of full-length lamin proteins owing to their non-globular, rod-shaped structural conformation. Therefore, no structure of a full-length IF protein has yet been reported. Recombinant lamin purification is most commonly conducted through inclusion body solubilization, thus requiring denaturing and renaturing steps. Lamins intrinsically polymerize at high protein concentrations, which inhibits crystallization of the full-length protein. The size,

Purified Lamin Assembles into Filaments

Lamin assembles into filaments in a hierarchical fashion. Single lamin proteins form dimers, and these further assemble into head-to-tail polymers (Figure 2A). These polymers can interact laterally to form lamin tetramers (termed protofilaments) which show the characteristic beaded appearance of lamin assemblies. In vitro, these lamin protofilaments further assemble into filaments or to paracrystalline arrays, which are probably not relevant in a biological context 21, 22, 23. To date, only the

The Nuclear Lamina Is a Filamentous Meshwork Underlying the Inner Nuclear Membrane

EM studies of old rat liver cells showed an amorphous dense nuclear lamina present underneath the inner nuclear membrane [28]. The first insight into the filamentous organization of lamins came from native Xenopus laevis oocytes where lamin filaments of approximately 10 nm in diameter were observed using freeze-dried metal-shadowed EM [29]. The meshwork was shown to be quasi-regular, even in regions where the nuclear lamina had been adjacent to nuclear pore complexes (NPCs) [29]. Further studies

Lamin Isoforms Assemble into Separate Meshwork Structures

A glimpse of the supramolecular organization of lamins in mammalian somatic cells was provided by super-resolution microscopy studies. 3D-structured illumination microscopy (3D-SIM) analysis in mammalian nuclei revealed that each of the lamins A, C, B1, and B2 form distinctive separate meshworks (Figure 3A) [31]. Computational image analysis revealed some meshwork properties such as lamin edge length (0.432 μm of native lamin A in wild-type cells) and edge connectivity (four edges per face,

Proteins that Interact With Lamins

Both ex vivo and in vivo lamin filaments from C. elegans or mammalian lamins, respectively, show thinner filaments of the size of protofilaments compared to in vitro assembled lamin filaments or paracrystalline fibers. This could be due to lamin PTMs (Box 1) and/or interactions between lamins and their binding partners. There are hundreds of proteins that probably interact directly or indirectly with lamins at the nuclear lamina. These include mostly INM (inner nuclear membrane) proteins and

Concluding Remarks

Nuclear lamins are essential components of nuclear architecture. Studies of their structure in somatic cells and in C. elegans have shown that they are organized as a meshwork of protofilaments, and for this reason the diameter of lamin filaments is smaller than that of other cellular filaments. Each major lamin isoform forms a separate meshwork. The structure–function relationships of lamins are now being facilitated through insights into the mechanisms underlying the laminopathies.

Many

Acknowledgments

This work was funded by grants from the Swiss National Science Foundation Grant (SNSF 31003A_159706/1) and the Mäxi Foundation (to O.M.), and GIF I-1289-412.13/2015 (to Y.G. and O.M.). We thank the Center for Microscopy and Image Analysis at the University of Zurich (ZMB).

Glossary

3D-structured illumination microscopy (3D-SIM)
super-resolution microscopy technique which makes use of the nonlinear response of fluorophores.
Cryo-electron microscopy (cryo-EM)
transmission electron microscopy (TEM) carried out at cryogenic temperatures. Allows high-resolution structural analysis of vitrified molecules and samples.
Cryo-electron tomography (cryo-ET)
the vitrified sample is kept at cryogenic temperatures. Cryo-ET is applied to reconstruct 3D volumes of the sample at high resolution.

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