STRUCTURE DETERMINATION OF TAHO

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tankyrases 1 and 2 (TaHO) are telomere-associated proteins with poly(ADP-ribose) polymerase (PARP) activity that positively regulate telomere length and may contribute to maintenance of telomere structure. Tankyrases use NAD+ as a substrate to catalyze formation of ADP-ribose polymers onto proteins including themselves. Tankyrase mediated poly(ADP- ribosyl)ation of the telomere binding protein TRF1 results in its release from telomeres and induces telomere elongation associated with cell proliferation. Tankyrase inhibition is expected to disrupt telomere structure, thereby causing chromosomal end fusions that result in cell death. The objective of this proposal is to determine the structure of the poly- ADP ribose polymerase (PARP) domain of a human homologue of tankyrase. A native data set has been collected to 3.0 Angstrom and molecular replacement has been extensively tested for structure solution. Heavy atom phasing information will be needed to determine the structure of this protein.