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TUBBY Domain

No ImageThe Tubby domain forms an unusual helix-filled b-barrel structure. A co-crystal of the Tubby domain in complex with GPMI-P2, an analog of the head group from phosphotidylinositol (4,5) biphosphate, reveals that phosphoinositide binding occurs in a basic pocket at one end of the putative DNA binding groove. Amino acid side chains involved in interactions with GMPI-P2 are primarily in b-strands 4, 5 and 6 and helix 6A. A central feature of the binding interface is Lysine-330 that coordinates between the 4- and 5- position phosphates providing high selectivity for phosphatidyl inositides that are phosphorylated on adjacent positions of the inositol ring.

Structure Reference:
Santagata, S. et al. (2001) Science. 292(5524): 2041-2050. PDB: 1I7E.

Domain binding and function:
The Tubby domain was first identified in the tubby protein implicated in mature-onset obesity. Spanning approximately 260 amino acids, the Tubby domain has a remarkable dual binding function as it is capable of interacting with both DNA and phosphotidylinositol. The Tubby domain of the tubby and TULP proteins binds with high specificity to biphosphorylated phosphoinositides that are phosphorylated at the 4-position on the inositol ring, such as PI(4,5)P2. This allows the Tubby domain to function downstream of receptors such as the 5HT2C serotonin receptor. 5HT2C activation leads to stimulation of trimeric G-proteins that activate phospholipase C (PLC). PLC hydrolysis of PI(4,5)P2 releases the Tubby domain from the membrane, from whence it tranlocates into the nucleus. Once in the nucleus, the Tubby domain binds DNA allowing the tubby protein amino-terminal transcription factor-like activation domain to promote transcription.
Examples of Proteins: 
TUBBY Domain Proteins
Binding Partners
Tubby PI(4,5)P2; PI(3,4)P2

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