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Tubby domain

Class: Phospholipid Binding

Brief description: Tubby-like proteins (TULPs) were discovered by identification of a mutation at the tubby (tub) locus, which causes obesity and neusensory degradation. Located at the C-terminus of all TULPs, Tubby domains are approximately 260 residues long and are highly conserved domain. They are located at the COOH-terminus and do not exhibit homolgy to other known proteins. At least four tubby-like proteins are conserved across different species of mammals and other multicellular organisms. The tubby domains have been shown to bind some IP2 (PtdIns(4,5)P2, PtdIns(3,4)P2) and IP3 (PtdIns(3,4,5)P3) but not others (PtdIns(3,5)P2).

Structure:

structure From the X-ray structure of the Tub tubby domain, it was shown that the domain displays 12-stranded antiparallel beta-barrel conformation that is filled with a central a-helix. The PtdIns(4,5)P2-binding site is formed between three beta-strands and an external helix. It has also been proposed that its binding mode is similar to that of the CALM ANTH domain. Mutations of cationic residues involved in PtdIns(4,5)P2 binding have been shown to disrupt the plasma membrane localization of the tubby domain. Although further studies are needed to elucidate the membrane-binding mechanism, it seems that the domain would only interact with the IP2 headgroup while staying on the surface of ghe bilayer.

Subcellular Localization:

The tubby domain sequesters the TULP away from its effectors that are located in the nucleus by PtdIns(4,5)P2-mediated plasma membrane binding. So, in contrast to other membrane-targeting domains whose membrane binding leads to the activation of their host proteins, membrane binding of tubby domains serves to keep their host proteins dormant.

Get the sequences in a Swiss-Prot/Uniprot pattern and Tab-delimited format.

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Relevant Literature

1. Carroll, K., Gomez, C. and Shapiro, L. (2004) Tubby proteins: the plot thickens. Nat Rev Mol Cell Biol, 5, 55-63.

2. Ikeda, S., He, W., Ikeda, A., Naggert, J.K., North, M.A. and Nishina, P.M. (1999) Cell-specific expression of tubby gene family members (tub, Tulp1,2, and 3) in the retina. Invest Ophthalmol Vis Sci, 40, 2706-2712.

3. Cantley, L.C. (2001) Transcription. Translocating tubby. Science, 292, 2019-2021.

4. Cho, W. and Stahelin, R.V. (2005) Membrane-protein interactions in cell signaling and membrane trafficking. Annu Rev Biophys Biomol Struct, 34, 119-151.