PROSITE documentation PDOC50086 [for PROSITE entry PS50086]

TBC/rab GAP domain profile





Description

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 [1]. The connection of this domain with rab GTPase activation stems from subsequent in-depth sequence analyses and alignments [2] and recent work demonstrating that it appears to contain the catalytic activities of the yeast rab GAPs, GYP1, and GYP7 [3]. 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 [4].

The TBC/rab GAP domain contains six conserved motifs named A to F [2]. A conserved arginine residue in the sequence motif B has been shown to be critical for the full GAP activity [3]. 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 [5].

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 [6].

The profile we developed covers the entire six conserved motifs of the TBC/rab GAP domain.

Last update:

October 2002 / First entry.

Technical section

PROSITE method (with tools and information) covered by this documentation:

TBC_RABGAP, PS50086; TBC/rab GAP domain profile  (MATRIX)


References

1AuthorsRichardson P.M., Zon L.I.
TitleMolecular cloning of a cDNA with a novel domain present in the tre-2 oncogene and the yeast cell cycle regulators BUB2 and cdc16.
SourceOncogene 11:1139-1148(1995).
PubMed ID7566974

2AuthorsNeuwald A.F.
TitleA shared domain between a spindle assembly checkpoint protein and Ypt/Rab-specific GTPase-activators.
SourceTrends Biochem. Sci. 22:243-244(1997).
PubMed ID9255064

3AuthorsAlbert S., Will E., Gallwitz D.
TitleIdentification of the catalytic domains and their functionally critical arginine residues of two yeast GTPase-activating proteins specific for Ypt/Rab transport GTPases.
SourceEMBO J. 18:5216-5225(1999).
PubMed ID10508155
DOI10.1093/emboj/18.19.5216

4AuthorsZhang S.-D., Kassis J., Olde B., Mellerick D.M., Odenwald W.F.
TitlePollux, a novel Drosophila adhesion molecule, belongs to a family of proteins expressed in plants, yeast, nematodes, and man.
SourceGenes Dev. 10:1108-1119(1996).
PubMed ID8654926

5AuthorsRak A., Fedorov R., Alexandrov K., Albert S., Goody R.S., Gallwitz D., Scheidig A.J.
TitleCrystal structure of the GAP domain of Gyp1p: first insights into interaction with Ypt/Rab proteins.
SourceEMBO J. 19:5105-5113(2000).
PubMed ID11013213
DOI10.1093/emboj/19.19.5105

6AuthorsReczek D., Bretscher A.
TitleIdentification of EPI64, a TBC/rabGAP domain-containing microvillar protein that binds to the first PDZ domain of EBP50 and E3KARP.
SourceJ. Cell Biol. 153:191-206(2001).
PubMed ID11285285



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