Transglutaminase 2 Undergoes A Large Conformational Change Upon Activation

The transglutaminase family of enzymes is best known for crosslinking
proteins to form networks that strengthen tissues. Although this enzyme
family
has been extensively studied, a detailed understanding of the catalytic
mechanism has been hampered by the lack of a structure in which the enzyme
is
active.

This week in the open-access journal PLoS Biology, Daniel Pinkas,
Chaitan Khosla, and colleagues show how they have solved, at atomic
resolution, the structure of transglutaminase 2 (TG2) in complex with a
molecule that mimics a natural substrate. The structure exposes the active
site, giving direct insights into the catalytic mechanism. Unexpectedly,
they observed a very large conformational change with respect to previous
transglutaminase structures. Very few proteins have been observed to
undergo this type of large-scale transformation.

They propose a role for
this
structural rearrangement in the early stages of celiac disease, an
autoimmune disorder in which TG2 is the principal auto-antigen. Besides
the
fundamental implications, these results should allow for the rational
design of better inhibitors of TG2 for pharmacological and therapeutic
purposes.



Citation: Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase
2 undergoes a large conformational change upon activation. PLoS Biol
5(12):
e327. doi:10.1371/journal.pbio.0050327
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