The ~200 amino acid TBC/rab GTPase-activating protein (GAP) domain is well
conserved across species and has been found in a wide range of different
proteins from plant adhesion molecules to mammalian oncogenes. The name TBC
derives from the name of the murine protein Tbc1 in which this domain was
first identified based on its similarity to sequences in the tre-2 oncogene,
and the yeast regulators of mitosis, BUB2 and cdc16 . The connection of
this domain with rab GTPase activation stems from subsequent in-depth sequence
analyses and alignments  and recent work demonstrating that it appears to
contain the catalytic activities of the yeast rab GAPs, GYP1, and GYP7 .
The TBC/rab GAP domain has also been named PTM after three proteins known to
contain it: the Drosophila pollux, the human oncoprotein TRE17 (oncoTRE17),
and a myeloid cell line-expressed protein .
The TBC/rab GAP domain contains six conserved motifs named A to F . A
conserved arginine residue in the sequence motif B has been shown to be
critical for the full GAP activity . Resolution of the 3D structure of the
TBC/rab GAP domain of GYP1 has shown that it is a fully α-helical V-shaped
molecule (see <PDB:1FKM>). The conserved arginine residue is positioned at the
side of the narrow cleft on the concave site of the V-shaped molecule. It has
been proposed that this cleft is the binding site for the GTPase. The
conserved arginine residue probably functions as a catalytic arginine finger
analogous to that seen in ras and Rho-GAPs. The two key features of the
arginine finger activation mechanism appear to be (i) the positioning of the
catalytically essential GTPase glutamine side chain via a hydrogen bonding
interaction between the glutamine carbamoyl-NH2 group and the main chain
carbonyl group of the GAP arginine, and (ii) the polarization of the γ-phosphate group or the stabilization of charge on it via the interaction of
the positively charged side chain guanidinoyl group of the GAP arginine .
Some proteins known to contain a TBC/rab GAP domain are listed below:
Yeast mitotic check point protein BUB2. BUB2 monitors spindle microtubule
assembly during mitosis.
Yeast GTPase-activating proteins (GAPs) GYP 1 to 7. GAPs enhance the
inherently slow GTPase activity of Ras-like proteins, which function as
binary molecular switches controlling cellular pathways.
Yeast MIC1 protein.
Fission yeast cell division control protein 16 (CDC16). It is part of a
checkpoint control system regulating septum formation.
Drosophila pollux, an adhesion molecule.
Mammalian rab GAPs.
Human TRE oncogene protein.
Human EBP50-PDZ interactor of 64 kDa (EPI64). It binds to the first PDZ
domain of EBP50 and E3KARP .
The profile we developed covers the entire six conserved motifs of the
TBC/rab GAP domain.
October 2002 / First entry.
PROSITE method (with tools and information) covered by this documentation:
Richardson P.M. Zon L.I.
Molecular cloning of a cDNA with a novel domain present in the tre-2 oncogene and the yeast cell cycle regulators BUB2 and cdc16.
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