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J Biol Chem, Vol. 274, Issue 41, 29050-29056, October 8, 1999
From the Institut für Pharmakologie und Toxikologie der
Universität Freiburg, Hermann-Herder-Strasse 5, D-79104
Freiburg, Germany
The small GTPases Rho, Rac, and Cdc42 are
monoglucosylated at effector domain amino acid threonine 37/35 by
Clostridium difficile toxins A and B. Glucosylation renders
the Rho proteins inactive by inhibiting effector coupling. To
understand the functional consequences, effects of glucosylation on
subcellular distribution and cycling of Rho GTPases between cytosol and
membranes were analyzed. In intact cells and in cell lysates,
glucosylation leads to a translocation of the majority of RhoA GTPase
to the membranes whereas a minor fraction is monomeric in the cytosol
without being complexed with the guanine nucleotide dissociation
inhibitor (GDI-1). Rho complexed with GDI-1 is not substrate for
glucosylation, and modified Rho does not bind to GDI-1. However, a
membranous factor inducing release of Rho from the GDI complex makes
cytosolic Rho available as a substrate for glucosylation. The binding
of glucosylated RhoA to the plasma membranes is saturable, competable
with unmodified Rho-GTP
Monoglucosylation of RhoA at Threonine 37 Blocks
Cytosol-Membrane Cycling
S guanosine
5'-O-(3-thiotriphosphate), and takes place at a membrane
protein with a molecular mass of about 70 kDa. Membrane-bound glucosylated Rho is not extractable by GDI-1 as unmodified Rho is,
leading to accumulation of modified Rho at membranous binding sites.
Thus, in addition to effector coupling inhibition, glucosylation also
inhibits Rho cycling between cytosol and membranes, a prerequisite for
Rho activation.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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