The evolutionarily conserved Dim1 protein defines a novel branch of the thioredoxin fold superfamily

Dim1 is a small evolutionarily conserved protein essential for G2/M transit ion that has recently been implicated as a component of the mRNA splicing m achinery. To date, the mechanism of Dim1 function remains poorly defined, i n part because of the absence of informative sequence homologies between Di m1 and other functionally defined proteins or protein domains. We have used a combination of molecular modeling and NMR structural analysis to demonst rate that similar to 125 of the 142 amino acids of human Dim1 (hDim1) defin e a novel branch of the thioredoxin fold superfamily. Mutational analysis o f Dim1 based on the predicted fold indicates that alterations in the region corresponding to the thioredoxin active site do not affect Dim1 activity. However, removal of a very short carboxyterminal extension generates a domi nant negative form of the protein [hDim1-( 1- 128)] that when overproduced induces cell cycle arrest in G2, via a mechanism likely to involve alterati on of Dim1 association with partner molecules. In sum, this study identifie s the Dim1 proteins as a novel sixth branch of the thioredoxin superfamily involved in cell cycle.