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Transglutaminases: crosslinking enzymes with pleiotropic functions

Key Points

  • Transglutaminases (TGs) are Ca2+-dependent enzymes that post-translationally modify specific glutaminyl (Gln) side-chains in proteins by deamidation, transamidation or esterification.

  • Notwithstanding active-centre similarities with the papain family of cysteine proteases, structural as well as kinetic features set TGs apart as a separate superfamily of enzymes that are widely distributed in nature.

  • The human genome encodes eight TGs; at least one of these, TG2, is regulated by GTP/GDP and could function in signal transduction. Another protein, erythrocyte band 4.2, is a catalytically inactive member of the TG family and functions as a scaffolding protein.

  • Independent of its catalytic activity, TG2 can also form tight multipartite complexes with fibronectin and integrins; a role that is important for cell spreading and migration and for extracellular matrix (wound healing) organization.

  • TG-catalysed transamidation between glutamine and lysine residues can lead to the formation of covalent side-chain bridges between protein units; in this sense, TGs function as nature's catalysts to glue proteins together, and so to generate crosslinked supramolecular protein assemblies.

  • Blood clotting, skin-barrier and bone formation are some well-known examples of the physiological role of TGs; crosslinking might also be important in the maturation of pathological insoluble protein aggregates, and in apoptosis.

  • Genetic deficiencies of these enzymes are known to cause severe bleeding and skin disorders, and in several autoimmune diseases (including the gluten sensitivity diseases) a TG is the main — if not the sole — autoantigen.

Abstract

Blood coagulation, skin-barrier formation, hardening of the fertilization envelope, extracellular-matrix assembly and other important biological processes are dependent on the rapid generation of covalent crosslinks between proteins. These reactions — which are catalysed by transglutaminases — endow the resulting supramolecular structure with extra rigidity and resistance against proteolytic degradation. Some transglutaminases function as molecular switches in cytoskeletal scaffolding and modulate protein–protein interactions. Having knowledge of these enzymes is essential for understanding the aetiologies of diverse hereditary diseases of the blood and skin, and various autoimmune, inflammatory and degenerative conditions.

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Figure 1: Transglutaminases catalyse various post-translational reactions.
Figure 2: Transglutaminase-catalysed protein polymerization and 'spotwelding' of assemblies.
Figure 3: Alignment of the catalytic-domain regions of transglutaminases and other structurally-characterized papain-like enzymes.
Figure 4: Genomic organization, protein domains and tertiary structure of transglutaminases.
Figure 5: Phylogenetic tree of papain-like transglutaminases.
Figure 6: Activation of human fXIII zymogen.
Figure 7: TG2-mediated crosslinking of the membrane skeleton of human erythrocytes.
Figure 8: TG2 mediates cell–matrix interactions and also promotes mineralization.
Figure 9: Transglutaminases stabilize dermo–epidermal junctions.

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Acknowledgements

We are extremely grateful to D. Aeschlimann and D. B. Rifkin for their help, to M. Santos Lozano and colleagues for sharing unpublished data on the maize TG sequences, to M. Wouters for allowing us to include unpublished phylogenetic and structural insights into the TG superfamily, to L. Zanetti and L. Cariello for the sequence of sea urchin TG. We would also like to thank R. P. Riek and P. T. Velasco for their assistance with some of the figures, and S. Iismaa for her critical reading of this manuscript.

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Correspondence to Laszlo Lorand.

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DATABASES

Entrez

cytotoxic factor

necrotoxin

Swiss-Prot

erythrocyte band 4.2

fXIIIa

Sea bream TG

TG1

TG2

TG3

TG4

TG5

TG7

FURTHER INFORMATION

Robert M. Graham's laboratory

Glossary

KERATINOCYTE

A differentiated epithelial cell of the skin.

RHO FAMILY GTPASES

Ras-related GTPases that are involved in controlling the polymerization of actin.

STRESS FIBRES

Bundles of microfilaments and other proteins that are found commonly on migrating cells. They are contractile and can be anchored to a focal adhesion.

ERYTHROPOIESIS

The formation of red blood cells in bone marrow and elsewhere.

ZYMOGEN

An inactive precursor of an enzyme from which the active enzyme is generated by a conformational change in the structure, which is brought about by ligand binding or by a specific chemical modification such as cleavage of the zymogen polypeptide chain.

BUCCAL EPITHELIAL CELL

An epithelial cell of the inner lining of the cheek.

MEGAKARYOCYTE

A large (40–150μm), highly polyploid bone-marrow cell — budding of its cytoplasm gives rise to platelets.

PLASMODIUM

The motile multinucleate mass of protoplasm, which is bounded by a plasma membrane, that is made by the true slime moulds.

MACROPHAGE

A tissue-resident cell that is derived from circulating monocytes that have the ability to phagocytose foreign particulate and colloidal material.

ASTROCYTE

A star-shaped glial cell that supports the tissue of the central nervous system.

PLATELETS

The smallest non-nucleated blood cells, which are derived from megakaryocytes, that are important in haemostasis and blood coagulation.

CHONDROCYTE

A differentiated cell of cartilage tissue.

KAPOSI'S SARCOMA

An angiogenic tumour that is composed of endothelial and spindle cells (elongated fibroblast-like shaped cells that usually express endothelial markers).

IONOPHORE

A substance (natural or synthetic, cyclic or linear) that can bind ions in solution and transport them across lipid barriers in natural or artificial membranes.

STRATUM CORNEUM

The outer layer of epidermis of vertebrate skin.

OPACIFICATION

The clouding of the lens that reduces visual acuity. It results from the disruption of the ordered crystalline structure of lens proteins that normally allows the unhindered passage of light.

NEUROBLASTOMA CELLS

An immortalized cell line that is derived from tumours that arise from the neural crest.

HYDROXYAPATITE

(Crystalline calcium phosphate). A mineral component of bone.

GLIADINS

A family of proline-and glutamine-rich proteins that are the principal toxic component of wheat gluten.

TAU

A neuronal protein that binds to microtubules and promotes their assembly and stability.

POLYTOMIES

Internal nodes of a cladogram that each have more than two immediate descendents (that is, sister taxa).

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Lorand, L., Graham, R. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4, 140–156 (2003). https://doi.org/10.1038/nrm1014

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