DCoH functions as a metabolic enzyme in the cytoplasm and a transcriptional co-activator in the nucleus. These two functions appear to be unrelated. DCoH has no nuclear localization signal of its own, and enters the nucleus after interacting with HNF-1. We are investigating how the cytoplasmic DCoH pool partitions into its two functions.

The DCoH oligomerization switch: As an enzyme, DCoH is a tetramer. As a co-activator, a DCoH dimer interacts with an HNF-1a dimer (see Figure). The DCoH homotetramer is hyperstable, but the stability of a DCoH paralog, DCoH2, is less stable. In order to characterize how DCoH partitions between its enzymatic and coactivator populations in the cell, we are measuring the relative stabilities of the DCoH homotetramers and the DCoH/HNF-1a complexes. We are also addressing if these two functions of DCoH are mutually exclusive, by investigating if the DCoH/HNF-1a complex is enzymatically active.

We are initerested in how stabilization of HNF-1a dimers by DCoH modulates HNF-1a activity. In particular, we are testing how DCoH contributes to the susceptibility of HNF-1a to diabetes-associated mutations.