Lamins: the structure and protein complexes

Lamins: the structure and protein complexesYosef Gruenbaum1 and Ohad Medalia2,3

Available online at www.sciencedirect.com

ScienceDirect

Lamins are nuclear intermediate filament (IF) proteins. They

assemble to fibrous structures that are positioned between the

inner nuclear membrane and the peripheral chromatin. A small

fraction of lamins is also present in the nucleoplasm. Lamins are

required to maintain the nuclear structure and, together with

their associated proteins, are involved in most nuclear

activities. Mutations in lamins cause >14 distinct diseases,

called laminopathies, that include heart, muscle, fat and early

aging diseases. However, it is not clear how lamins are

organized in vivo and how the disease mutations affect lamin

organization and functions. Here, we will review structural

aspects of lamin assembly, discuss differences between

peripheral and nucleoplasmic lamins and describe the protein

complexes that lamins form.

Addresses1 Department of Genetics, Institute of Life Sciences, Hebrew University

of Jerusalem, Jerusalem 91904, Israel2 Department of Biochemistry, Zurich University, Winterthurerstrasse

190, CH-8057 Zurich, Switzerland3 Department of Life Sciences and National Institute for Biotechnology

in the Negev, Ben-Gurion University, Beer-Sheeva 84120, Israel

Corresponding authors: Gruenbaum, Yosef ([email protected]) and

Medalia, Ohad ([email protected])

Current Opinion in Cell Biology 2015, 32:7–12

This review comes from a themed issue on Cell architecture

Edited by Sandrine Etienne-Manneville and Elly M Hol

http://dx.doi.org/10.1016/j.ceb.2014.09.009

0955-0674/# 2014 Elsevier Ltd. All rights reserved.

IntroductionLamins, the major cytoskeleton component of animal

nuclei, are the only nuclear intermediate filament

proteins [1]. Their number has increased in metazoan

evolution from a single lamin gene in hydra and

nematodes to two lamin genes in Drosophila and to

3–5 genes in vertebrates [2]. Humans have three

lamin genes, termed LMNA (encoding lamins A, C,

D10 and C2), LMNB1 (encoding lamin B1) and

LMNB2 (encoding lamins B2 and B3). LMNA gene

is expressed in differentiated cells, while at least one

lamin B gene is expressed in every somatic cell in the

body. Recent data suggest that the different lamins

form separate filamentous networks that interact with

one another [3].

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Lamins are classified as type V intermediate filament

proteins [4]. Like all IFs, lamins consist of an amino-

terminal head domain, a coiled-coil central rod domain

and a carboxy-terminal tail domain. Their unique features

include a nuclear localization signal (NLS), an Ig-fold

domain and a CaaX motif (C = cysteine, a = aliphatic

residues, X = any residue). The lamin gene is thought

to be the ancestral gene of all IF genes, since all metazoa

express lamins including those that do not express cyto-

plasmic IFs. In addition, a lamin-like homologue contain-

ing a coiled-coil domain, an Ig domain and a CaaX motif,

is expressed at the nuclear envelope in the unicellular

organism Dictyostelium discoideum [5]. Furthermore, all

lamins contain an extra six heptad repeats in coil 1B that

are absent in vertebrate cytoplasmic IFs, and at least one

B-type lamin gene is expressed in every metazoan cell,

while cytoplasmic IFs show tissue-specific and cell-

specific pattern of expression [1].

The structure of lamins and laminaarchitectureThe lamin filamentous meshwork was first seen at the

nuclear periphery using transmission electron microscopy

[6]. Scanning electron microscopy images of nuclear

envelopes derived from Xenopus laevis oocyte revealed

organized filaments underlining the inner nuclear mem-

brane (INM) [7]. These images are still the preferred

model of choice to describe the organization of nuclear

lamins within the lamina, despite the time which past and

advancement in imaging technologies [8]. While these

images represent the organization of lamin LIII, which is

expressed in the germline of fish, amphibians, reptile and

birds [9], the organization of the lamin network in somatic

cells is still elusive. A growing evidence indicates that

different lamins form separate networks that interact with

each other [10,11]. It is still not clear how lamin A, lamin

C, lamin B1 and lamin B2 assemble into the lamina

network, whether they form layers on top of each other

or fully integrate into one single meshwork, and how they

are interconnected with inner nuclear membrane (INM)

proteins, as well as with the peripheral heterochromatin is

yet to be revealed. Advanced nanometer-resolution ima-

ging technologies may provide a deeper understanding of

how lamins assemble and organize within the mammalian

lamina and generate important insights into related struc-

ture-function relationships.

An in vitro assembly model of the lamin of Caenorhabditiselegans (Ce-lamin) protein, based on cryo electron tom-

ography studies, suggested a hierarchal order of assembly

wherein lamins first form dimers, which then polymerize

to form a polar head-to-tail linear polymer. Next, lateral


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8 Cell architecture

assembly of two head-to-tail polymers forms a four mol-

ecule wide protofilament (Figure 1A). Interestingly,

interactions of lateral adjacent lamin dimers are sup-

ported by the X-ray structural determination of coil

2 of human lamin A [12�]. Finally, the non-polar proto-

filaments further assemble into IF-like, 10 nm filaments,

composed of three or four protofilaments [13�](Figure 1A).

High-resolution analysis of proteins typically involves invitro structural analysis. However, IF-proteins impose a

challenge for structural studies since these are elongated

proteins and readily polymerize in concentrated solutions.

Therefore X-ray crystallography could not be employed

for structural determination of the proteins. Moreover,

lamins, as well as other cytoplasmic IFs, can only be

purified under denaturing conditions, since they resist

more native conditions. When lamins are reconstituted in

more physiological conditions, they readily assemble

into high molecular structures, which circumvent high-

resolution structural determination. A way to override this

Figure 1

protofilament

21 nm27 nm

(c)(b)

(a)

2 head-to-tail polymers

dimer

Current Opinion in Cell Biology

Lamin assembly in vitro and ex vivo. (a) Structural elements of lamin

assembly. Lamin polypeptides assembled into dimers and associate

longitudinally to form polar head-to-tail polymer structures. Two head-

to-tail polymers interact laterally in an anti-parallel fashion to form

protofilaments. In C. elegans, the head-to-tail polymers are staggered

21 nm apart, forming the pattern of alternating 21 nm and 27 nm

between paired globular tail domains, within a protofilament. (b, c) The

nuclear lamina formed by C. elegans lamin in Xenopus laevis oocyte. (b)

A surface-rendered tomogram showing Ce-lamin organization underling

the Xenopus nuclear envelope. Lamin protofilaments are depicted in

yellow, NPCs in red. The volume displays

1310 nm � 1310 nm � 409 nm. (c) A variety of protofilament interactions

enable formation of the irregular meshwork structure.


obstacle was to crystalize small domains of lamin. X-ray

crystallography and NMR studies revealed that the struc-

ture of the globular C-terminal domain of lamin A

resembles the immunoglobulin (Ig) structure [14,15].

This Ig-fold domain consists of 116 residues folded into

a b-sandwich of nine b-strands. The core of this globular

domain is formed by hydrophobic residues, with most

charged residues appearing at the surface of the domain,

thereby allowing for interactions with other proteins or

with DNA. The coiled-coil domain of lamin A was

structurally analyzed in pieces. Initially, structural

analysis of the human lamin A supported the involvement

of coil 2 of the rod domain in the overlap head-to-tail

dimers interactions between two sequential dimers

within head-to-tail polymer of dimer allowing a parallel

and polar assembly (Figure 1A) [16�]. Moreover, the

crystallographic analysis of a different fragment contain-

ing coil 2 of human lamin A revealed two anti-parallel

coiled-coil with a weak dimerization propensity that can

potentially be assembled into both parallel and antipar-

allel dimers [12�]. Besides the typical heptad repeats of

lamin coiled-coil domains, repeats of every 15 amino acids

are probably involved in the antiparallel interactions

between lateral, adjacent of head-to-tail polymer of

lamin dimers. These structural analyses described the

molecular interactions that play a role in larger lamin

assemblies. They further demonstrated that the coiled-

coil helices of lamins could potentially form hetero-

geneous structures that may be fundamental for lamin

physiological roles.

In living cells, lamins are embedded in the dense envi-

ronment of the nuclear envelope where they intimately

interact with heterochromatin, INM proteins, nuclear

pore complex (NPC) proteins and nuclear peripheral

proteins. Hence, imaging lamin filaments requires their

isolation from nuclear membranes and heterochromatin.

Unfortunately, these procedures necessitate harsh treat-

ment of the sample that might cause artifacts. Alterna-

tively, lamin filaments can be imaged within their native

environment if they can be distinguished within the

crowded nuclear envelope environment. As an intermedi-

ate step to understand lamin assembly in vivo, Ce-lamin

was ectopically expressed ex vivo in Xenopus laevisoocytes. Using minimal purification steps on physically

isolated nuclear envelopes that are free of chromatin and

other adhering material, cryo-electron tomography was

applied. These experiments revealed that Ce-lamin

assembles into flexible protofilaments that interacts with

each other and exhibit a diameter of 5–6 nm (Figure 1B

and C) [17�]. These data show that protofilaments are the

basic assembly units in vivo and that they can assemble

into thicker, higher order, filaments. Therefore, the

10 nm IF-like lamin filament structure represents only

one form of assembly out of several assembly possibilities.

The ability of proto-filaments to interact in many con-

formations may play a role in providing the unique


Lamins: the structure and protein complexes Gruenbaum and Medalia 9

mechano-stability of a nucleus and can easily adapt to

resist the functional requirements and mechanical stres-

ses applied on nuclei.

Lamins in the nuclear interiorAntibodies directed against mammalian A-type and B-

type lamins stain the nuclear periphery occasionally

showing a veil (for A-type lamins) or dots (for B-type

lamins) in the nucleoplasm. This ‘residual’ nucleoplasmic

staining of lamins was regarded for a long time as an

artifact of immuno-staining procedures and it was there-

fore assumed that lamins are present only at the nuclear

periphery. Later, novel antibodies and analyses of GFP-

lamin fusion proteins revealed the authenticity of the

presence of the lamins in the nucleoplasm [3,18–21]. A

first genetic proof for the presence of nucleoplasmic lamin

was obtained in C. elegans nuclei, which are partially down

regulated for Ce-lamin. In that study, both peripheral and

nucleoplasmic Ce-lamin were down regulated to almost

the same extent [22].

In mammalian cells, about 10% of A-type lamins are

soluble with low detergent concentrations [23,24]. The

presence of lamin A in the nucleoplasm depends on its

protein partner lamina associated protein 2a (LAP2a).

The loss of both nucleoplasmic lamin A and the soluble

fraction of lamin A in cells derived from LAP2a knockout

mice suggests that the nucleoplasmic fraction of lamin A

is the soluble fraction, which can form structures that are

different from the peripheral lamins. These nucleoplas-

mic structures are organized, presumably, as a separated

proteinaceous network that is more susceptible to protein

extraction [23]. A recent study has mapped the phosphor-

ylation sites in lamin A and suggests that phosphorylation

at Ser22 and Ser392 in vertebrate lamins A/C, which flank

the rod domain from both sides, is involved in solubilizing

lamin A in the nucleoplasm [25�].

A small fraction of B-type lamins is also present in the

nucleoplasm where its Ig-fold domain interacts directly

with, and is required for, the activity of proliferating cell

nuclear antigen (PCNA) and is required for DNA replica-

tion [19,26]. In contrast to nucleoplasmic A-type lamins,

there is no soluble fraction of lamin B1 [27] and only

minute amounts of lamin B2 are present in a soluble

fraction of HeLa cells. Similarly, the nucleoplasmic Ce-

lamin is insoluble [22,24], further highlighting the differ-

ences in the organizational states of A-type and B-type

lamins.

In both human and C. elegans cells, all peripheral lamins

are highly immobile with mean residence times of several

hours as shown by fluorescence recovery after photo-

bleaching (FRAP), fluorescence loss in photobleaching

(FLIP) and fluorescence correlation spectroscopy (FCS)

[11,25�,27–29]. However, while the nucleoplasmic

C. elegans lamin remains highly immobile with a mean


residence time of over an hour, as shown by FRAP and

FCS analysis (Y.G. personal communication and [29]), a

large fraction of the mammalian nucleoplasmic A-type

lamins is replaced within a few seconds [28]. Likewise,

FCS analyses of GFP-lamin A in HeLa cells revealed two

mobile nucleoplasmic fractions with diffusion coefficients

of 5.0 � 0.3 mm2/s and 0.38 � 0.04 mm2/s, indicating a

mobile and a less mobile lamin population, respectively.

Similar values were observed for GFP-lamin C. However,

a small nucleoplasmic fraction of �10% of both lamins A

and C were shown to be immobile [11,28].

It is likely that the highly dynamic fraction of the nucleo-

plasmic lamins represent intermediate states of lamins on

their way to being incorporated in the peripheral lamina

meshwork. This fraction of A-type lamins can also serve

as a potential reservoir for protein turnover, similar to

what has been found for cytoplasmic IFs [30]. In addition,

elegant studies have shown that nucleoplasmic lamins

have specific important roles, for example, the nucleo-

plasmic A-type lamins interact with LAP2a and this

complex is involved in the cell-cycle regulation and

tumor-suppression through interaction with protein reti-

noblastoma (pRb) [31]. In addition, although lamin A

does not accumulate at sites of DNA damage, induced

DNA breakage reduces the mobility of nucleoplasmic A-

type lamins, which is required for stabilizing DNA

damage repair foci in mammalian nuclei [32]. Interest-

ingly, the small nucleoplasmic fraction of B-type lamins

is highly immobile [27]. These data may suggest an

indirect involvement of lamin A in the process of DNA

repair.

Lamin protein complexesLamins are involved in a variety of stable and transient

interactions at both the INM and within the nucleo-

plasm. Most of the known lamin-binding proteins, esti-

mated to be >100, are integral proteins of the INM [33].

Initially, lamin partners were identified since they were

either linked to lamin-associated human diseases or

were immuno-localized to the nuclear envelope. These

lamin associated proteins interact with lamins either

directly or indirectly (reviewed in [34,35]), and many

of them share common protein domains, such as the

LEM domain [36,37] and the SUN domain [38–40]

(Figure 2). The analysis of the lamin proteome/inter-

actome is hindered by the fact that the peripheral lamins

are very stable and are biochemically insoluble, there-

fore can hardly be purified. A recent study utilized a

novel technique that overcomes the problem of identi-

fying lamin-interacting proteins in vivo, termed BioID

[41]. Human lamin A was fused to a promiscuous bac-

terial biotin ligase. Proteins in the proximity of lamin A

were biotinylated, affinity isolated and identified by

mass spectrometry [42�]. This analysis unveiled novel

lamin-binding proteins, as well as a partial set of known

lamin associated proteins.


10 Cell architecture

Figure 2

IF MT

MT

Torsin A/B

Actin

Dynein

NPC

SUN

LBR

HP1Actin

Titan

Peripheral lamin B Peripheral la

min A/C

Chrom

atin

Internal lamin B

Nespr

in1/

2

Centro

some

KinesinPlectin

Nes

prin

3

Internal lamin A/C

Current Opinion in Cell Biology

Lamins and their binding partners. Illustration depicting the known interactions of lamins with INM proteins, nuclear pores and nucleoplasmic factors.

The peripheral lamin A and B and the nucleoplasmic lamins are depicted. The filamentous nature of the lamins in the nucleoplasm remains

hypothetical. MT, microtubules; IF, intermediate filaments; GCL, germ cell-less; BAF, barrier to autointegration factor; pRB, retinoblastoma protein;

LBR, lamin B receptor. The blue color marks the nucleoplasm.

The composition of integral proteins of the nuclear mem-

brane is tissue-specific and cell-specific [33]. The latter

observation suggests that the composition of lamin com-

plexes changes during development and differentiation.

Additionally, a recent study shows that the amounts of

lamin A, but not lamin B, depends on cell fate [43��].Therefore, analyzing both lamin A and lamin B protein

complexes in different cell types is critical for under-

standing the roles of lamins in the different cell functions.

ConclusionsNuclear lamins are essential structural components of

nuclear architecture and are involved in most nuclear

functions. Studies of their structure and the protein

complexes that they form are now being facilitated

through advances in biochemical, biophysical and pro-

teomic techniques and are analyzed with novel genetic

tools. These studies provide insights into the mechanisms


of laminopathies that are caused by a large number of

mutations in the LMNA gene, as well as in genes encoding

lamin A processing proteins or genes encoding lamin-

binding partners.

Many interesting properties of the lamins remain to be

determined. These include the molecular structure of the

different lamin filament networks and how they interact

with one another, the roles of the different types of lamin

assemblies both within the lamina and throughout the

nucleoplasm, the roles of the different lamins in regulat-

ing chromatin organization and the roles of lamins in

aging and metabolism.

Since the nuclear lamina forms a densely packed structure

containing proteins and chromatin, structural investigation

of lamin networks in situ still remains a challenging task.

Development of new tools in biochemistry, imaging and


Lamins: the structure and protein complexes Gruenbaum and Medalia 11

structural techniques, such as high-resolution detectors for

cryo-ET and super-resolution fluorescence microscopy, in

combination with established methods, will likely provide

unprecedented view of lamins in the near future. Inte-

grative approaches, including high resolution structural

determination of lamins in vitro and analysis of lamins in

model organism such as C. elegans will extend our knowl-

edge on the lamin organization in living cells and will

ultimately help to understand how mutations in these

proteins alter the lamin network and network interactions,

thereby causing various diseases.

AcknowledgementsWe gratefully acknowledge Noam Zuela for Figure 2, Amnon Buxboim andmembers of the Gruenbaum and Medalia groups for discussions, andfunding from the Morasha Legacy 1798/10, the Muscular DystrophyAssociation (MDA), the Israeli Science Foundation, the Binational Israel-USA Science Foundation (BSF 2007215), the Niedersachsen-IsraeliResearch Cooperation program to Y.G. and a Swiss National ScienceFoundation grant (SNSF 31003A_141083/1) to O.M. and the COSTNANONET (BM1002) to YG and OM.

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Lamins: the structure and protein complexes