Molecular Locomotion: Modeling the Functional Domains of E1 Helicase to Assess the Asymmetric Rotary Model of E1 Helicase

Abstract

Helicases are highly conserved enzymes that unwind the double helix of DNA, providing access to single‐stranded DNA. Found in all living organisms and viruses, helicases function as motor proteins in replication, transcription, and remodeling of DNA. A common sexually‐transmitted oncovirus, human papillomavirus (HPV) uses E1 helicase, the most studied helicase protein because of the ease by which it can be isolated. The only enzyme encoded in the HPV episome, E1 hexameric helicase is a ring‐shaped translocase that belongs to the AAA+ family and superfamily 3. E1 has near exact rotational symmetry with respect to its six subunits. Each monomer comprises a central five‐stranded anti‐parallel beta‐sheet and six alpha helices. Conserved sequence motifs Walker A and B and an arginine finger participate in the binding and hydrolysis of ATP causing conformational changes in β‐hairpins, powering the walking movement along the ssDNA. Assembling first as a double‐trimer at the replication origin and then into two homohexamers on opposing strands, E1 separates the dsDNA into ssDNA by occlusion in the 3'→5' direction. Asymmetric sequential progression of ATP hydrolysis around the hexameric ring at catalytic sites between monomers powers translocation of E1. An understanding of its functional domains and how they interact with each other, DNA, and host proteins is necessary to elucidate the overall mechanism of helicase function. Using 3D printing technology, The Governor's Academy SMART (Students Modeling A Research Topic) Team modeled the E1 helicase to provide vital insight into the mechanism of eukaryotic DNA replication and potentially promote development of therapeutic treatments.