Summary: Tub family
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This is the Wikipedia entry entitled "Tubby protein". More...
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Tubby protein Edit Wikipedia article
A tubby protein expressed in mouse brain
|SCOPe||1c8z / SUPFAM|
The tubby protein is encoded by the TUB gene. It is an upstream cell signaling protein common to multicellular eukaryotes. The first tubby gene was identified in mice, and proteins that are homologous to tubby are known as "tubby-like proteins" (TULPs). They share a common and characteristic tertiary structure that consists of a beta barrel packed around an alpha helix in the central pore. The gene derives its name from its role in metabolism; mice with a mutated tubby gene develop delayed-onset obesity, sensorineural hearing loss and retinal degeneration.
Tubby proteins are classified as Î±+Î² proteins and have a 12-beta stranded barrel surrounding a central alpha helix. Tubby proteins can bind the small cell signaling molecule phosphatidylinositol, which is typically localized to the cell membrane. A similar structural fold to the Tubby like proteins has been identified in the Scramblase family of proteins.
Tubby proteins have been implicated as transcription factors and as potential signaling factors coupled to G-protein activity. They are associated with neuronal differentiation and development, and in mammals are implicated in three disease processes when mutated: obesity, retinal degeneration, and hearing loss. In mice, mutations in tubby proteins are known to affect life span and fat storage as well as carbohydrate metabolism. Tubby domains associate with cytoplasmic side of cell membranes through binding of different phosphoinositides
Human proteins containing this domain
- Noben-Trauth, K.; Naggert, J. K.; North, M. A.; Nishina, P. M. (1996). "A candidate gene for the mouse mutation tubby". Nature. 380 (6574): 534â€“538. Bibcode:1996Natur.380..534N. doi:10.1038/380534a0. PMID 8606774.
- Kleyn, P. W.; Fan, W.; Kovats, S. G.; Lee, J. J.; Pulido, J. C.; Wu, Y.; Berkemeier, L. R.; Misumi, D. J.; Holmgren, L.; Charlat, O.; Woolf, E. A.; Tayber, O.; Brody, T.; Shu, P.; Hawkins, F.; Kennedy, B.; Baldini, L.; Ebeling, C.; Alperin, G. D.; Deeds, J.; Lakey, N. D.; Culpepper, J.; Chen, H.; GlÃ¼cksmann-Kuis, M. A.; Carlson, G. A.; Duyk, G. M.; Moore, K. J. (1996). "Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family". Cell. 85 (2): 281â€“290. doi:10.1016/S0092-8674(00)81104-6. PMID 8612280.
- Ohlemiller, KK; Hughes, RM; Mosinger-Ogilvie, J; Speck, JD; Grosof, DH; Silverman, MS (1995). "Cochlear and retinal degeneration in the tubby mouse". NeuroReport. 6 (6): 845â€“9. doi:10.1097/00001756-199504190-00005. PMID 7612867.
- Bateman A, Finn RD, Sims PJ, Wiedmer T, Biegert A, SÃ¶ding J (January 2009). "Phospholipid scramblases and Tubby-like proteins belong to a new superfamily of membrane tethered transcription factors". Bioinformatics. 25 (2): 159â€“62. doi:10.1093/bioinformatics/btn595. PMC 2639001. PMID 19010806.
- Boggon, TJ; Shan, WS; Santagata, S; Myers, SC; Shapiro, L (1999). "Implication of tubby proteins as transcription factors by structure-based functional analysis". Science. 286 (5447): 2119â€“25. doi:10.1126/science.286.5447.2119. PMID 10591637.
- Carroll, K; Gomez, C; Shapiro, L (2004). "Tubby proteins: the plot thickens". Nat Rev Mol Cell Biol. 5 (1): 55â€“63. doi:10.1038/nrm1278.
- Mukhopadhyay, A; Deplancke, B; Walhout, AJ; Tissenbaum, HA (2005). "C. elegans tubby regulates life span and fat storage by two independent mechanisms". Cell Metab. 2 (1): 35â€“42. doi:10.1016/j.cmet.2005.06.004.
- Wang, Y; Seburn, K; Bechtel, L; Lee, BY; Szatkiewicz, JP; Nishina, PM; Naggert, JK (2006). "Defective carbohydrate metabolism in mice homozygous for the tubby mutation". Physiol Genomics.
- Cho, W. & Stahelin, R.V. (June 2005). "Membrane-protein interactions in cell signaling and membrane trafficking" (abstract page). Annual Review of Biophysics and Biomolecular Structure. 34: 119â€“151. doi:10.1146/annurev.biophys.33.110502.133337. PMID 15869386. Retrieved 2007-01-23.
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Tub family Provide feedback
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Internal database links
|Similarity to PfamA using HHSearch:||DUF3527|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000007
Tubby, an autosomal recessive mutation, mapping to mouse chromosome 7, was recently found to be the result of a splicing defect in a novel gene with unknown function. This mutation maps to the tub gene [PUBMED:8612280, PUBMED:8606774]. The mouse tubby mutation is the cause of maturity-onset obesity, insulin resistance and sensory deficits. By contrast with the rapid juvenile-onset weight gain seen in diabetes (db) and obese (ob) mice, obesity in tubby mice develops gradually, and strongly resembles the late-onset obesity observed in the human population. Excessive deposition of adipose tissue culminates in a two-fold increase of body weight. Tubby mice also suffer retinal degeneration and neurosensory hearing loss. The tripartite character of the tubby phenotype is highly similar to human obesity syndromes, such as Alstrom and Bardet-Biedl. Although these phenotypes indicate a vital role for tubby proteins, no biochemical function has yet been ascribed to any family member [PUBMED:10591637], although it has been suggested that the phenotypic features of tubby mice may be the result of cellular apoptosis triggered by expression of the mutated tub gene. TUB is the founding-member of the tubby-like proteins, the TULPs. TULPs are found in multicellular organisms from both the plant and animal kingdoms. Ablation of members of this protein family cause disease phenotypes that are indicative of their importance in nervous-system function and development [PUBMED:14708010].
Mammalian TUB is a hydrophilic protein of ~500 residues. The N-terminal (INTERPRO) portion of the protein is conserved neither in length nor sequence, but, in TUB, contains the nuclear localisation signal and may have transcriptional-activation activity. The C-terminal 250 residues are highly conserved. The C-terminal extremity contains a cysteine residue that might play an important role in the normal functioning of these proteins. The crystal structure of the C-terminal core domain from mouse tubby has been determined to 1.9A resolution. This domain is arranged as a 12-stranded, all anti-parallel, closed beta-barrel that surrounds a central alpha helix, (which is at the extreme carboxyl terminus of the protein) that forms most of the hydrophobic core. Structural analyses suggest that TULPs constitute a unique family of bipartite transcription factors [PUBMED:10591637].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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This superfamily contains the scramblase protein family, the Tub family and the DUF567, a family of plant and bacterial proteins of hitherto unknown function. All members are membrane-tethered transcription factors.
The clan contains the following 4 members:DUF3527 LOR Scramblase Tub
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:
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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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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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.
|Author:||Finn RD , Bateman A|
|Number in seed:||132|
|Number in full:||3693|
|Average length of the domain:||232.80 aa|
|Average identity of full alignment:||36 %|
|Average coverage of the sequence by the domain:||45.25 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 Tub domain has been found. There are 7 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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