3-DIMENSIONAL STRUCTURE OF THE BIFUNCTIONAL PROTEIN PCD DCOH, A CYTOPLASMIC ENZYME INTERACTING WITH TRANSCRIPTION FACTOR HNF1/

The bifunctional protein pterin-4a-carbinolamine dehydratase (PCD)/dim erization cofactor of HNF1 (DCoH) is a cytoplasmic enzyme involved in the tetrahydrobiopterin regeneration and is found in complex with the transcription factor HNF1 in liver cell nuclei, An atypical hyperpheny lalaninemia and the depigmentation disorder vitiligo are related to a deficiency of PCD/DCoH activity, The crystal structure of PCD/DCoH was solved by multiple isomorphous replacement and refined to a crystallo graphic R-factor of 20.5% at 2.7 Angstrom resolution, The single domai n monomer comprises three alpha-helices packed against one side of a f our-stranded, antiparallel beta-sheet, The functional enzyme is a homo -tetramer of 222 symmetry where each of the monomers contributes one h elix to a central four helix bundle, In the tetramer two monomers form an eight-stranded, antiparallel beta-sheet with six helices packing a gainst it from one side. The concave, hydrophobic surface of the eight -stranded beta-sheet with its two protruding loops at either end is re miniscent of the saddle-like shape seen in the TATA-box binding protei n, PCD/DCoH binds as a dimer to the helical dimerization domain of dim eric HNF1 forming a hetero-tetramer possibly through a mixed four heli x bundle.