Dimerization Rules of Mammalian PAS Proteins

The PAS (PER, ARNT, SIM) protein family plays a vital role in mammalian biology and human disease. This analysis arose from an interest in the signaling mechanics by the Ah receptor (AHR) and the Ah receptor nuclear translocator (ARNT). After more than fifty years by studying this and related mammalian sensor systems, describing the role of PAS domains in signal transduction is still challenging. In this perspective, we attempt to interpret recent studies of mammalian PAS protein structure and consider how this new insight might explain how these domains are employed in human signal transduction with an eye towards developing strategies to target and engineer these molecules for a new generation of therapeutics. Our approach is to integrate our understanding of PAS protein history, cell biology, and molecular biology with recent structural discoveries to help explain the mechanics of mammalian PAS protein signaling. As a learning set, we focus on sequences and crystal structures of mammalian PAS protein dimers that can be visualized using readily available software.