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7  structures 166  species 1  interaction 847  sequences 23  architectures

Family: Tub (PF01167)

Summary: Tub family

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This is the Wikipedia entry entitled "Tubby protein". More...

Tubby protein Edit Wikipedia article

Tubby Protein
Tubby-1c8z-pymol.png
A tubby protein expressed in mouse brain
Identifiers
Symbol Tub
Pfam PF01167
InterPro IPR000007
PROSITE PDOC00923
SCOP 1c8z
SUPERFAMILY 1c8z
OPM superfamily 177
OPM protein 1i7e

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.[1][2][3]

Structure

Tubby proteins are classified as α+β 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.[4]

Function

Tubby proteins have been implicated as transcription factors[5] and as potential signaling factors coupled to G-protein activity.[6] 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.[5] In mice, mutations in tubby proteins are known to affect life span and fat storage[7] as well as carbohydrate metabolism.[8] Tubby domains associate with cytoplasmic side of cell membranes through binding of different phosphoinositides[9]

Human proteins containing this domain

TUB; TULP1; TULP2; TULP3; TULP4;

External links

References

  1. ^ Noben-Trauth, K.; Naggert, J. K.; North, M. A.; Nishina, P. M. (1996). "A candidate gene for the mouse mutation tubby". Nature 380 (6574): 534–538. Bibcode:1996Natur.380..534N. doi:10.1038/380534a0. PMID 8606774.  edit
  2. ^ 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.; Glücksmann-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): 281–290. doi:10.1016/S0092-8674(00)81104-6. PMID 8612280.  edit
  3. ^ 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): 845–9. doi:10.1097/00001756-199504190-00005. PMID 7612867.  edit
  4. ^ Bateman A, Finn RD, Sims PJ, Wiedmer T, Biegert A, Söding J (January 2009). "Phospholipid scramblases and Tubby-like proteins belong to a new superfamily of membrane tethered transcription factors". Bioinformatics 25 (2): 159–62. doi:10.1093/bioinformatics/btn595. PMC 2639001. PMID 19010806. 
  5. ^ a b 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):2119-25.
  6. ^ Carroll K, Gomez C, Shapiro L. (2004). Tubby proteins: the plot thickens. Nat Rev Mol Cell Biol5(1):55-63.
  7. ^ 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):35-42.
  8. ^ 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 Epub.
  9. ^ Cho, W. and Stahelin, R.V. (June 2005). "Membrane-protein interactions in cell signaling and membrane trafficking" (abstract page). Annual Review of Biophysics and Biomolecular Structure 34: 119–151. doi:10.1146/annurev.biophys.33.110502.133337. PMID 15869386. Retrieved 2007-01-23. 

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Internal database links

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].

Domain organisation

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

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Pfam Clan

This family is a member of clan Tubby_C (CL0395), which has the following description:

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 3 members:

Scramblase Tub Tub_2

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 using the family HMM. We also generate alignments using four representative proteomes (RP) sets, 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
(11)
Full
(847)
Representative proteomes NCBI
(787)
Meta
(14)
RP15
(172)
RP35
(275)
RP55
(391)
RP75
(509)
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Format an alignment

  Seed
(11)
Full
(847)
Representative proteomes NCBI
(787)
Meta
(14)
RP15
(172)
RP35
(275)
RP55
(391)
RP75
(509)
Alignment:
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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
(11)
Full
(847)
Representative proteomes NCBI
(787)
Meta
(14)
RP15
(172)
RP35
(275)
RP55
(391)
RP75
(509)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped 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.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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.

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: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD, Bateman A
Number in seed: 11
Number in full: 847
Average length of the domain: 217.80 aa
Average identity of full alignment: 36 %
Average coverage of the sequence by the domain: 43.04 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 20.6
Trusted cut-off 20.7 21.0
Noise cut-off 20.2 20.5
Model length: 246
Family (HMM) version: 13
Download: download the raw HMM for this family

Species distribution

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Interactions

There is 1 interaction for this family. More...

Tub

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 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 seqence.

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