Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
39  structures 1579  species 0  interactions 45249  sequences 680  architectures

Family: RabGAP-TBC (PF00566)

Summary: Rab-GTPase-TBC domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "TBC domain". More...

TBC domain Edit Wikipedia article

The TBC (Tre-2/Bub2/Cdc16) is identified as a domain of some proteins or as a protein motif and widely recognized as a conserved one that includes approximately 200 amino acids in all eukaryotes.


TBC was initially identified as a conserved domain among the tre-2 oncogene product and the yeast cell cycle regulators. It has been shown that humans have almost 42 different TBC proteins which differ from each other by having additional motifs and domains (GRAM, RUN, PTB…) and add functional diversification to the family . The most well known of this protein group are TBC1D1 and TBC1D4 which are directly associated with functional diseases. Moreover, most of them have really close relations with other protein domains. For example, it has been demonstrated that some of them act like a GAP (GTPase-activating protein) for small GTPases: Rab activity is modulated in part by GTPase-activating proteins (GAPs) and many of these RabGAPs share a Tre2/Bub2/Cdc16(TBC)-domain architecture. However, it is needed much research on these kind of proteins and in this article it explains what is known by now.

Picture 1. A Rab Cycle in membrane trafficking: The cycle between the GTP-bound inactive state and the GTP- bound active state is led by the Rab protein and regulated by an activating enzyme GEF[1] and an inactivating enzyme GAP which in this case could be the TBC protein. Hereafter, the activated form of Rab, GTP-bound, is incorporated to a specific organelle or vesicle and promotes its transport by interacting with a specific effector molecule. GTPase-activating proteins (GAPs) limit the duration of the active state and accelerate the slow intrinsic rate of GTP hydrolysis.


TBC mainly functions as a specific Rab GAP (GTPases activating proteins) by being used as tools to inactivate specific membrane trafficking events. GAPs serve to increase GTPase activity by contributing the residues to the active site and promoting conversion from GTP to GDP form. Such activity of TBC proteins does not always require a close physical interaction although few TBC proteins have shown clear GAP activity towards their binding Rabs.[2] Rab families contribute to defining organelles and controlling specificity and rate of transport through individual pathways. Therefore, TBC Rab-GAPS are essential regulators of intracellular and membrane transports as well as central participants in signal transduction. Nevertheless, not all TBC may have a primary role as a Rab-GAP and conversely, not all Rab-GAP contain TBC. In addition, the fact that this family has been poorly studied makes it then further complicated.

Evolution and research

Phylogenetic analysis has provided insight into the evolution of the TBC family. ScrollSaw was implemented as a recent strategy to overcome poor resolution between TBC genes found in standard phylogenetic strategies during initial reconstructions.[3] Significantly, the TBC domain is nearly always smaller than the Rab cohort in any individual genome, suggesting Rab/TBC coevolution. Twenty-one putative TBC sub-classes were founded and identified as a seven robust and two moderately supported clades.

Moreover, there has also been systematic analysis in order to identify the target Rabs of TBC proteins. It was, at first, based on the physical interaction between the TBC domain and its substrate Rab. For instance Barr and his coworkers found a specific interaction between RUTBC3/RabGAP-5 and Rab5A that activates the GTPase activity of Rab5 isoform. Similarly other research has shown that, among other important aspects, the TBC-Rab interaction alone is insufficient to determine the target of TBC proteins. However, there has been a second approach to identifying the target Rabs of TBC by investigating their in vitro GAP activity. Yet there has been similar discrepancies between this findings of different investigators which can be found in literature and may be attributable to differences between methods of in vitro. In addition, research has shown that TBC proteins are associated with some human diseases. For example, a dysfunction of TBC1D1 and TBC1D4 directly affects insulin actions and glucose uptake. Causing overweight or leanness due to the fact that this two family members of TBC regulate insulin-stimulated GLUT4 translocation to the plasma membrane in mammals. Furthermore, many of them have been shown to be associated with cancer, but the exact mechanism by which they are associated with this illness remains largely unknown. Therefore, there’s still much research needed to be done on this biological topic.


  1. ^ Rowlands AG, Panniers R, Henshaw EC (1988). "The catalytic mechanism of guanine nucleotide exchange factor action and competitive inhibition by phosphorylated eukaryotic initiation factor 2". The Journal of Biological Chemistry. 263 (12): 5526–33. PMID 3356695.
  2. ^ Bos JL, Rehmann H, Wittinghofer A (2007). "GEFs and GAPs: critical elements in the control of small G proteins". Cell. 129 (5): 865–77. doi:10.1016/j.cell.2007.05.018. PMID 17540168.
  3. ^ Gabernet-Castello C, O'Reilly AJ, Dacks JB, Field MC (2013). "Evolution of Tre-2/Bub2/Cdc16 (TBC) Rab GTPase-activating proteins". Molecular Biology of the Cell. 24 (10): 1574–83. doi:10.1091/mbc.E12-07-0557. PMC 3655817. PMID 23485563.

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Rab-GTPase-TBC domain Provide feedback

Identification of a TBC domain in GYP6_YEAST and GYP7_YEAST, which are GTPase activator proteins of yeast Ypt6 and Ypt7, implies that these domains are GTPase activator proteins of Rab-like small GTPases.

Literature references

  1. Richardson PM, Zon LI; , Oncogene 1995;11:1139-1148.: Molecular cloning of a cDNA with a novel domain present in the tre-2 oncogene and the yeast cell cycle regulators BUB2 and cdc16. PUBMED:7566974 EPMC:7566974

  2. Neuwald AF; , Trends Biochem Sci 1997;22:243-244.: A shared domain between a spindle assembly checkpoint protein and Ypt/Rab-specific GTPase-activators. PUBMED:9255064 EPMC:9255064

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000195

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 [ PUBMED:7566974 ]. The connection of this domain with rab GTPase activation stems from subsequent in-depth sequence analyses and alignments [ PUBMED:9255064 ] and recent work demonstrating that it appears to contain the catalytic activities of the yeast rab GAPs, GYP1, and GYP7 [ PUBMED:10508155 ].

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 [ PUBMED:8654926 ]. The TBC/rab GAP domain contains six conserved motifs named A to F [ PUBMED:9255064 ]. A conserved arginine residue in the sequence motif B has been shown to be critical for the full GAP activity [ PUBMED:10508155 ]. Resolution of the 3D structure of the TBC/rab GAP domain of GYP1 has shown that it is a fully alpha-helical V-shaped molecule. 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 gamma-phosphate group or the stabilization of charge on it via the interaction of the positively charged side chain guanidinoyl group of the GAP arginine [ PUBMED:11013213 ].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

Representative proteomes UniProt
Jalview View  View  View  View  View  View  View 
HTML View             
PP/heatmap 1            

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

Representative proteomes UniProt

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Representative proteomes UniProt
Raw Stockholm Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Alignment kindly provided by SMART
Previous IDs: TBC;
Type: Family
Sequence Ontology: SO:0100021
Author: SMART
Number in seed: 69
Number in full: 45249
Average length of the domain: 196.50 aa
Average identity of full alignment: 20 %
Average coverage of the sequence by the domain: 28.05 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 24.5 24.5
Trusted cut-off 24.5 24.5
Noise cut-off 24.4 24.4
Model length: 216
Family (HMM) version: 21
Download: download the raw HMM for this family

Species distribution

Sunburst controls


Weight segments by...

Change the size of the sunburst


Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls


The tree shows the occurrence of this domain across different species. More...


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the RabGAP-TBC domain has been found. There are 39 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

Loading structure mapping...

AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A087WVF3 View 3D Structure Click here
A0A087WXS9 View 3D Structure Click here
A0A087X179 View 3D Structure Click here
A0A087X1G2 View 3D Structure Click here
A0A0G2JWM9 View 3D Structure Click here
A0A0G2K5B0 View 3D Structure Click here
A0A0G2K712 View 3D Structure Click here
A0A0G2K9K0 View 3D Structure Click here
A0A0G2K9M5 View 3D Structure Click here
A0A0G2K9Q0 View 3D Structure Click here
A0A0G2KLX0 View 3D Structure Click here
A0A0G2KPH4 View 3D Structure Click here
A0A0P0UX28 View 3D Structure Click here
A0A0P0VA26 View 3D Structure Click here
A0A0R0EUM4 View 3D Structure Click here
A0A0R0GFU0 View 3D Structure Click here
A0A0R0GZ87 View 3D Structure Click here
A0A0R0H032 View 3D Structure Click here
A0A0R0H896 View 3D Structure Click here
A0A0R0IQ79 View 3D Structure Click here
A0A0R0KBN0 View 3D Structure Click here
A0A0R4ICD0 View 3D Structure Click here
A0A0R4IHT5 View 3D Structure Click here
A0A0R4IVP6 View 3D Structure Click here
A0A0R4IYT6 View 3D Structure Click here
A0A0U1RS33 View 3D Structure Click here
A0A144A0A3 View 3D Structure Click here
A0A164D380 View 3D Structure Click here
A0A1D6ETJ6 View 3D Structure Click here
A0A1D6G6S0 View 3D Structure Click here
A0A1D6GMM9 View 3D Structure Click here
A0A1D6HNX5 View 3D Structure Click here
A0A1D6I995 View 3D Structure Click here
A0A1D6IDR2 View 3D Structure Click here
A0A1D6J5D9 View 3D Structure Click here
A0A1D6JYQ7 View 3D Structure Click here
A0A1D6KJH7 View 3D Structure Click here
A0A1D6KN84 View 3D Structure Click here
A0A1D6M666 View 3D Structure Click here
A0A1D6MPB2 View 3D Structure Click here