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30  structures 823  species 2  interactions 16217  sequences 350  architectures

Family: RabGAP-TBC (PF00566)

Summary: Rab-GTPase-TBC domain

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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.

Ovreview

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.

Functions

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.

References

  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 3655817Freely accessible. 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


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000195

Identification of a TBC domain in GYP6_YEAST and GYP7_YEAST, which are GTPase activator proteins of yeast Ypt6 and Ypt7, imply that these domains are GTPase activator proteins of Rab-like small GTPases [PUBMED:11013213].

Domain organisation

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

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Alignments

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, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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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.

  Seed
(72)
Full
(16217)
Representative proteomes UniProt
(24399)
NCBI
(39251)
Meta
(79)
RP15
(4270)
RP35
(8310)
RP55
(12282)
RP75
(15259)
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Key: ✓ available, x not generated, not available.

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  Seed
(72)
Full
(16217)
Representative proteomes UniProt
(24399)
NCBI
(39251)
Meta
(79)
RP15
(4270)
RP35
(8310)
RP55
(12282)
RP75
(15259)
Alignment:
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Order:
Sequence:
Gaps:
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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.

  Seed
(72)
Full
(16217)
Representative proteomes UniProt
(24399)
NCBI
(39251)
Meta
(79)
RP15
(4270)
RP35
(8310)
RP55
(12282)
RP75
(15259)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   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...

Trees

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.

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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
Author: SMART
Number in seed: 72
Number in full: 16217
Average length of the domain: 195.70 aa
Average identity of full alignment: 20 %
Average coverage of the sequence by the domain: 29.34 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -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: 215
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
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Viroids Viroids Unclassified sequence Unclassified sequence

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Interactions

There are 2 interactions for this family. More...

Ras RabGAP-TBC

Structures

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 30 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.

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