Structural Biology of LINE-1 ORF2p: Progress and Outlook

Long Interspersed Element-1 (LINE-1) retrotransposons are mobile genetic elements that can move their locations through a “copy-and-paste” mechanism. LINE-1 mobility is catalyzed by ORF2p, a multifunctional enzyme that coordinates a complex reaction to reverse transcribe the LINE-1 mRNA into the genome. Since the discovery that LINE-1 is still active nearly four decades ago, a wealth of cellular, genomic, and biochemical studies has revealed the remarkable complexity of human LINE-1 biology. Yet, only within the past five years have structures of ORF2p complexes begun to illuminate the molecular mechanisms underlying its function. Here, we review recent advances in our structural and mechanistic understanding of ORF2p and highlight how new structural insights have reshaped models of LINE-1 retrotransposition. Finally, we explore how future structural studies may further illuminate the mechanisms of this remarkable retrotransposon.