534

Review

TRENDS in Biochemical Sciences Vol.27 No.10 October 2002

Transglutaminase 2: an enigmatic
enzyme with diverse functions
Laszlo Fesus and Mauro Piacentini
Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase that
catalyzes Ca2+-dependent protein modifications. It acts as a G protein in
transmembrane signalling and as a cell surface adhesion mediator, this
distinguishes it from other members of the transglutaminase family. The
sequence motifs and domains revealed in the recent TG2 structure, can each be
assigned distinct cellular functions, including the regulation of cytoskeleton,
cell adhesion and cell death. Ablation of TG2 in mice results in impaired wound
healing, autoimmunity and diabetes, reflecting the number and variety of
TG2 functions. An important role for the enzyme in the pathogenesis of coeliac
disease, fibrosis and neurodegenerative disorders has also been demonstrated,
making TG2 an important therapeutic target.

signalling, turned out to be TG2 [5]. TG2 binds and

hydrolyzes GTP with an affinity and catalytic rate
similar to the subunits of large heterotrimeric
G proteins and small Ras-type G proteins. Gh/TG2
couples 1b- and 1d- adrenoreceptors, thromboxane
and oxytocin receptors to phospholipase C (PLC1),
mediating inositol phosphate production in response
to agonist activation. The GDP/GTP-bound form
cannot act as a transglutaminase. This inhibition is
suspended by Ca2+, which serves as a switch between
the two distinct functions [6].

Published online: 12 September 2002

Structural explanation of biochemical functions

The first transglutaminase was identified by

Heinrich Waelsch more than 40 years ago as a liver
enzyme incorporating amines into proteins [1,2].
This enzyme, transglutaminase 2 (TG2), was used
to determine the catalytic mechanism of the
transglutaminases, which involves an active site
cysteine, the formation of an acyl-enzyme thioester
intermediate between this cysteine and a
polypeptide-bound glutamine and the reaction of the
thioester intermediate with a suitable nucleophile [3].
Because of their similarities in the catalytic triad and
reaction mechanism, transglutaminases
(EC 2.3.2.13), papain (EC 3.4.22.2) and papain-like
cysteine proteases are classified within the same
superfamily in the Structural Classification of
Proteins database (SCOP, http://scop.mrc-lmb.cam.
ac.uk/scop/). In invertebrates, only a single
transglutaminase gene has been found, whereas nine
evolutionary related genes (encoding blood
coagulation FXIIIa, TG17 and the inactive epb42),
clustered on five different chromosomes, have evolved
in vertebrates by successive duplications [4]. Human
TG2 is a 76-kD protein, consisting of 686 amino acids.
Laszlo Fesus*
Dept of Biochemistry and
Molecular Biology,
Faculty of Medicine,
Medical and Health
Science Center,
University of Debrecen,
H-4012 Hungary.
*e-mail: fesus@
indi.dote.hu
Mauro Piacentini
Dept of Biology,
University of Rome
Tor Vergata and
INMI-IRCCS Lazzaro
Spallanzani, Rome, Italy.

TG2 is a multifunctional protein

TG2 moonlights between several distinct

biochemical functions at various cellular locations
(for details see Fig. 1.) In addition to crosslinking,
TG2 can modify proteins by amine incorporation and
deamidation, and by acting as an isopeptidase in a
Ca2+-dependent manner (Fig. 1). Furthermore,
TG2 is externalized from cells, where it mediates
the interaction of integrins with fibronectin and
crosslinks proteins of the extracellular matrix (ECM).
In 1994, a novel G protein (Gh), observed in rat liver
plasma membrane as a mediator of transmembrane
http://tibs.trends.com

The structure of TG2, crystallized in a dimer form in

complex with GDP, has been reported recently [7].
Similar to another transglutaminase, FXIIIa [8], TG2
has four distinct domains (Fig. 2): an N-terminal
-sandwich (with fibronectin and integrin binding
site), catalytic core (containing the catalytic triad for
the acyl-transfer reaction and a conserved Trp
essential for this catalytic activity [9]) and two
C-terminal -barrel domains (the second contains a
phospholipase C binding sequence [10]).
A unique guanidine nucleotide-binding site, which
has not been found in any other protein, is located in a
cleft between the catalytic core and the first -barrel
[7]; this sequence is coded by exon 10 of the TG2 gene,
which has very poor sequence homology with the
same exons in other TGs. Some GDP/GTP-interacting
residues and those essential for GTP hydrolysis are
situated in other domains (Fig. 2), as predicted by
site-directed mutagenesis [11]. In the GDP-bound
form of TG2, access to the transamidation active site
is blocked by two loops, and the active site cysteine is
hydrogen-bonded to a Tyr residue [7].
The structure of the Ca2+-bound form of TG2 is
unresolved. A putative Ca2+-binding site, homologous
to one demonstrated in FXIIIa [12], is distorted in
the TG2 structure by the bound nucleotide [7].
Ca2+-binding at this site, or others [13], could weaken
nucleotide binding, and consequent conformational
changes a process which involves substrate binding
and related displacement of the hydrogen-bonded Tyr
[14] might make the active site accessible [15]. The
recently solved three dimensional structure of TG3 has
revealed that it has the same domain structure as TG2,
and after binding Ca2+ a channel opens to expose two
critical Trp residues that control access of substrates to
the active site [16]; similar structural changes might
occur in TG2. It has been suggested that the two

0968-0004/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0004(02)02182-5

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TRENDS in Biochemical Sciences Vol.27 No.10 October 2002

535

O
NH2-R

Gln

Glu

C, N, E

ar

m
ya

Ca2+

Pr o
-Cys

tein

-b

NH3

Incorporation of
amines into proteins

s
ine

r im

O
Gln

s
d Ly
oun

Glu

Lys

Lys

NH3

Crosslinking
of proteins

H2O

Gln

H2O

Glu

Site-specific
deamidation

NH3

H2 O

TG2

O
Glu

H2O

Lys

Glu

Lys

Isopeptidase
activity

Ca2+

Ca2+

Appearance on
the cell surface

Fibronectin
Promotion of
cellmatrix interactions

TG2

TG2
GDP
C

Integrins

GTP
E
Receptor
stimulation

Oxytocin receptor,
TP thromboxane A2 receptor,
1B- and 1D adrenoreceptors

GDP
VI
VII
I

III
II

V
IV

Transmembrane
signaling
PIP2

DAG

PLC-1
IP3

TG2
M
Fig. 1. Biochemical activities of transglutaminase 2 (TG2). TG2
catalyzes Ca2+-dependent acyl-transfer reaction [3] between
-carboxamide group of a specific protein-bound glutamine and either
the -amino group of a distinct protein-bound lysine residue (covalent
protein crosslinking; the principal in vivo activity) or primary amines
such as polyamines and histamine. Water can replace amine donor
substrates, leading to deamidation of the recognized glutamines. TG2,
similar to factor XIIIa, has Ca2+-dependent isopeptidase activity and,
at least under test tube conditions, can hydrolyse : isopeptides [55].
TG2 can be exposed on the external leaflet of the plasma
membrane ([40,42] and references therein). The presence of TG2
outside the cell has been proposed to depend on its interaction with
fibronectin and integrins [39,56,57]. TG2 binds and thereby activates
phospholipase C following stimulation of several kinds of cell surface
receptors; its endogenous GTPase activity ensures proper regulation of
transmembrane signalling through these receptors ([11] and references
therein). Functions of TG2 are performed in the cytosol (C), the nucleus
(N), at the cell membrane (M) and in the extracellular space (E). Except
for its isopeptidase activity, all other functions have been shown to
occur in intact cells and/or tissues.

non-proline cis peptide bonds (one close to the active site

cysteine) present in FXIIIa [17], TG2 [7] and TG3 [16]
might be involved in the activation process [17].
http://tibs.trends.com

GTP
Ti BS

Additional motifs of TG2 (Fig. 2) might be used to allow

externalization without a signal peptide, interaction
with integrins and fibronectin [18], and translocation
to the nucleus [19] or perhaps other organelles.
The function of TG2 in cells

How are the diverse biochemical activities of TG2

related to cellular functions? The in vivo expression
pattern of the enzyme, its subcellular locations and
identified substrates (Table 1) suggest multiple roles.
There are cell types (e.g. endothelial and smooth
muscle cells) which constitutively express TG2 at
high levels [20], whereas in other cell types it is
induced by distinct signalling pathways, targeting
specific response elements in the regulatory region of
the gene. Retinoic acid (RA), TGF, NF-B and AP
responsive sites and regions have been functionally
identified all are related to induction of cellular
defence mechanisms and cellular maturation ([21]
and references therein).

Review

536

-sandwich

(a)
1

TRENDS in Biochemical Sciences Vol.27 No.10 October 2002

-barrel1

Catalytic core

139 147

63

144

460 472

184

227

286

332

366

447

Exon10 538

-barrel2

583 472

592

687

639

687

COOH

NH2
K173
Y174

FN/Integrin

*BH3

W241 C277 H335 D358 N398 E447 R476 Y516

D400 E452 R478
273KY274 C336
387KY388
V479
M483

*NLS1

*Ca2+

GTP

R580
Y583

*NLS2

PLC1

(b)

Ti BS

Fig. 2. Functional elements and three-dimensional structure of the human tissue-type transglutaminase
(TG2) [7]. (a) The four structural domains are indicated by arrows with amino acid positions (top).
Exon boundaries of the gene encoding TG2 are indicated by arrowheads with numbers corresponding
to the last amino acids of each exon-encoded region. Exon 10, which contains residues forming the
GDP-binding site, is marked. Functional regions and amino acid positions indicated are as follows.
FN, fibronectin binding site [18], 2AEELVLE7 (cyan); integrin-binding region, N-terminal 28-kDa fragment;
BH3, BH3 motif of the Bcl-2 protein family, 200PKFLKNAGRDCSRR214 [34] (green); NLS1 and NLS2, nuclear
localization signals predicted on the basis of homology to the NLS of the NS1 non-structural protein of
influenza virus [19], 259DILRR263 and 597PKQKRK602 (grey); catalytic triad, Cys277-His335-Asp358 (blue) and
active site residues W241, C336 and Y516 of transamidating activity (purple ball and stick representation)
involved in transition state stabilization, forming an inhibitory H-bond with Cys277 and potential
inhibition of activity by disulfide bonding of Cys277, respectively [7,9,14]; Ca2+, Ca2+-binding site
predicted from the FXIIIa structure [12] (red); non-proline cis peptide bonds 273KY274, 387KY388 (yellow);
GTP, GDP-binding and GTPase catalytic site residues (orange); PLC1, interaction site for
phospholipase C1 657LHMGLHKLVVNFESDK LKAVK677 (magenta). Putative sites are labelled by an
asterisk. (b) Three-dimensional structure of TG2 in complex with GDP shown from directions facing
the transamidating (left) and the GTPase (right) active sites based on the reported crystal structure [7].
Functional regions indicated in (a) are coloured correspondingly. N- and C-terminals are designated
by N and C, respectively. The fibronectin binding site is not indicated because the revealed structure
lacks the coordinates for the N-terminal amino acids, M1L14. The catalytic triad and the surrounding
residues of the transamidating active site, as well as amino acids contributing to the GTPase site, are
shown in ball and stick representation. The bound GDP molecule is colored green. Clusters of Glu/Gln
and Asp/Asn residues forming putative Ca2+-binding sites predicted on the basis of surface
potentional analysis [13] are coloured red.

At membrane locations, the role of TG2 in

transmitting signals from seven-transmembrane
helix receptors to phospholipase C is clearly
established [11]. Phospholipase C itself becomes active
when its inhibition by GDPTG2 is suspended after
TG2 binds GTP [22]. Interaction of TG2 with specific
molecules (e.g. with sphingosylphosphocholine [23])
might reduce the Ca2+ requirement for the
http://tibs.trends.com

transglutaminase activity [24]. This activity is

strongly influenced by nitric oxide: up to 15 of the
18 cysteine residues can be nitrosylated and
denitrosylated in a Ca2+-dependent manner, inhibiting
and activating the enzyme, respectively [25].
TG2 activated by Ca2+ interacts with and modifies
major components of the cytoskeleton (Table 1).
In response to RA treatment, TG2-dependent
transamidation of RhoA results in the increased
binding of RhoA GTPase to ROCK-2 protein kinase,
autophosphorylation of ROCK-2 and phosphorylation
of vimentin [26] which can lead to the formation of
stress fibers and increased cell adhesion. These
events are prevented by TG2 inhibition. TG2 can
interact with -tubulin and with microtubule-binding
proteins [27] including tau, which can be crosslinked
by the enzyme [28].
An intriguing aspect of TG2 function is its
translocation to the nucleus under certain
conditions [24] presumably with the help of
importin-3 [19] where it can function either as a
G protein [29] or as a transamidase activated by
nuclear Ca2+-signals to crosslink histones [30],
retinoblastoma (Rb) [31] and SP1 (S. Kojima,
pers. commun.) proteins (Table 1). This suggests
that TG2 could have a direct role in chromatin
modifications and/or gene expression regulation.
TG2 is induced in cells undergoing apoptosis in vivo
[32]. Its overexpression primes cells for suicide and
inhibition of its expression by antisense strategy
results in decreased cell death [33]. It has been
reported recently that TG2 sensitizes cells for
apoptosis by interacting with mitochondria [34],
shifting them to a higher polarized state and altered
redox status. This might provoke activation of
transglutaminase crosslinking activity [24]. During
the late stage of apoptosis, the massive increase of
cytosolic Ca2+ determines the switch of TG2 to its
crosslinking configuration in all subcellular
compartments leading to extensive polymerization of
intracellular proteins (including actin [35] and Rb [31])
and formation of detergent-insoluble structures [36].
These protein scaffolds stabilize the structure of the
dying cell before its clearance by phagocytosis,
limiting the release of harmful intracellular
components and consequently inflammatory or
autoimmune responses [37]. Under pathological
conditions the death of cells expressing high amounts
of TG2 can occur as a result of a mummification event
caused by extensive crosslinking of cytosolic proteins
without signs of either apoptosis or necrosis [38].
TG2 on the cell surface and in the extracellular matrix

Integrin-bound TG2 on the cell surface provides a

binding site for fibronectin, which TG2 binds with
high affinity (Fig. 1). The TG2 binding site on
integrins probably involves sequences outside the
integrin ligand-binding pocket. It is estimated that,
on the surface of different cell types, 540% of 1
integrins could be complexed with TG2 and that all

Review

TRENDS in Biochemical Sciences Vol.27 No.10 October 2002

Table 1. Intracellular localization of TG2 and examples of its protein

a
partners
Subcellular compartment
Cytosol
Plasma membrane

Interacting proteins

Substrates

Receptors, PLC1 [11]

Integrins [39, 40]

RhoA [26], DLK [58]

LTGF- [59]
b
Ankyrin , LC1 [60]

Cytoskeleton
Microfilaments

Intermediate filaments
Microtubules

Tubulin- [27]

Nuclear

Importin 3 [19]

Actin [35], Myosin [61]

b
Spectrin , Thymosin [62]
b
Troponin T ,
b
b
Keratin , Vimentin
Neurofilaments [63]
S100A7, S100A10,
S100A11 [64]; Tau [28]
b
Histones
pRB [31]

Abbreviations: DLK, dual leucine zipper-bearing kinase; LTGF, latent tumor growth factor; LC1,
lipocortin; S100As, family of 1014 kDa EF hand containing calcium-binding proteins; pRB,
retinoblastoma protein; PLC, phospholipase.
b
For references see [65].

TG2 on the cell surface is present as 1:1 complexes

with integrins [39]. The interaction of TG2 with
integrins occurs primarily at the extracellular
domains of integrin subunits, does not require
crosslinking activity [40] and facilitates adhesion,
spreading and motility of cells [39,40].
The significance of TG2 function in the
extracellular space goes beyond promotion of cell
adhesion and spreading; it is directly involved in
wound healing and angiogenesis [41]. TG2 is also
involved in the assembly, remodelling and
stabilization of the ECM in various tissues [42]. This
is done by crosslinking fibronectin, fibrinogen/fibrin,
von Willebrand factor, vitronectin, lipoprotein a,
dermatane sulfate proteoglycans, collagen V,
osteonectin, laminin, nidogen and osteopontin ([42]
and references therein). Furthermore, the secreted
enzyme contributes to the covalent modification and
activation of several growth factors [43] including
TGF [44], which promotes transcriptional regulation
of ECM genes and of TG2 itself [45].
Consequences of TG2 deletion

Knowing the multifunctionality and unique cellular

biochemistry of TG2, it came as a surprise to learn
that homozygous deletion of TG2 does not result in an
embryonic lethal phenotype [46,47]. The homozygous
null animals are viable, of normal size and weight,
and born with mendelian frequency. No obvious
alterations have been observed in apoptosis, the
structure of the ECM or heart function (in which the
G protein activity of TG2 thought to be important).
The most probable explanation for the lack of severe
phenotypes is that other transglutaminases in
mammalian tissues can compensate for the loss
of TG2. However, the other mammalian
transglutaminases do not bind GDP/GTP and, with
the exception of FXIIIa, they have not been found on
the cell surface. Therefore, alterations are expected
http://tibs.trends.com

537

in TG2/ mice, especially under certain stresses and

pathological conditions. In fact, decreased adherence
of primary fibroblasts [47] and impaired wound
healing related to altered cytoskeletal dynamics of
fibroblasts [R. Graham, pers. commun.] have been
observed in these mice, consistent with the suggested
extra- and intra-cellular functions of TG2. The
participation of TG2 in apoptosis could explain the
findings that on increasing the frequency of cell
death in the knock out mice, clearance of apoptotic
cells by phagocytosis is defective in the thymus and
the liver and inflammatory as well as autoimmune
reactions develop (Z. Szondy, pers. commun.).
TG2-deficient mice also show glucose intolerance
and hyperglycaemia because of reduced insulin
secretion, a phenomenon similar to a subtype of
diabetes called MODY (for maturity-onset diabetes
of the young)[48]. In humans, no definitive TG2
deficiency has been observed so far, and therefore the
above findings clearly point to possible areas for
future clinical investigation.
Pathogenic role of the enzyme in disease

Coeliac disease is a malabsorbtion syndrome

characterized by almost total atrophy of villi in the
jejunum on exposure to dietary glutens. TG2 is involved
in generating T cell stimulatory gluten peptides
through deamidation of specific glutamines [49,50].
In HLA-DQ2 or HLA-DQ8 settings, the TG2-formed
disease-triggering epitopes provoke a pathological
immune response that destroys the jejunal
epithelium. In parallel, a T-cell-mediated
autoimmune response is initiated, producing
IgA-type autoantibodies against TG2 [51], the
detection of which has become a widely used
diagnostic marker of coeliac disease. Dysregulation
of the suggested functions of TG2 in various
pathological settings might significantly contribute
to the development of fibrosis in susceptible organs
such as the lung, liver and kidney ([52] and
references therein).
Huntington disease (HD) is a neurodegenerative
diseases caused by the expansion of CAG trinucleotide
repeats in the gene encoding huntingtin (htt). This
results in a large number of contiguous glutamine
residues in the htt protein. Accumulations of
ubiquitinated htt aggregate in the nucleus and
progressive loss of neuronal cells is observed. One of
the proposed mechanisms of htt aggregation is based
on the action of TG2 because expanded polyglutamine
repeats are excellent glutaminyl-donor substrates for
TG2-catalyzed cross-linking ([24] and references
therein). By crossing HD R6/1 transgenic mice with
TG2/ mice, a reduction in cell death was observed in
R6/1/TG2/ compared with TG2/ mice, together with
the potentiation of the formation of htt aggregates
and significant improvement in both motor
performance and survival [53], suggesting that the
involvement of TG2 in the loss of neurons in HD is not
related to the formation of htt aggregates.

538

Acknowledgements
This work was partially
supported by grants
(Apoptosis Mechanisms
and Apoclear) from the
European Community, by
funds from the Hungarian
National Research Fund
(OTKA) and Hungarian
Ministry of Health (ETT),
from AIRC and Ricerca
Corrente and Finalizzata
from the Italian Ministry
of Health. We thank
Zoltan Nemes and Zsolt
Keresztessy (University of
Debrecen) for their helpful
suggestions.

Review

TRENDS in Biochemical Sciences Vol.27 No.10 October 2002

Intronexon swapping of TG2 mRNA in the brains

of patients with Alzheimer disease results in the
appearance of an alternatively spliced short form of
TG2, which lacks GDP/GTP binding residues and
thereby has increased crosslinking activity [54].
The latter has been connected to the formation of
neurofibrillary tangles and death of neuronal cells [24].
Conclusion

TG2 is emerging as a well-characterized,

multifunctional molecular player in various cellular
processes, ranging from intracellular signalling to
apoptosis and pathological conditions such as
autoimmune and Huntington diseases. The evidence
accumulated in recent years points to the enzyme
having a general protective and stabilizing role in
cells and tissues; in fact, in the absence of the enzyme
mice show impaired wound healing, autoimmunity
and diabetes. However, under pathological condition,
the uncontrolled activation of TG2 can turn its

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