Biochemical Principles in Prion-Based Inheritance.

Prions are proteins that can stably fold into alternative structures that frequently alter their activities. They can self-template their alternate structures and are inherited across cell divisions and generations. While they have been studied for more than four decades, their enigmatic nature has limited their discovery. In the last decade, we have learned just how widespread they are in nature, the many beneficial phenotypes that they confer, while also learning more about their structures and modes of inheritance. Here, we provide a brief review of the biochemical principles of prion proteins, including their sequences, characteristics and structures, and what is known about how they self-template, citing examples from multiple organisms. Prion-based inheritance is the most understudied segment of epigenetics. Here, we lay a biochemical foundation and share a framework for how to define these molecules, as new examples are unearthed throughout nature.

Dimerization of visual pigments in vivo.

It is a deeply engrained notion that the visual pigment rhodopsin signals light as a monomer, even though many G protein-coupled receptors are now known to exist and function as dimers. Nonetheless, recent studies (albeit all in vitro) have suggested that rhodopsin and its chromophore-free apoprotein, R-opsin, may indeed exist as a homodimer in rod disk membranes. Given the overwhelmingly strong historical context, the crucial remaining question, therefore, is whether pigment dimerization truly exists naturally and what function this dimerization may serve. We addressed this question in vivo with a unique mouse line (S-opsin(+)Lrat(-/-)) expressing, transgenically, short-wavelength-sensitive cone opsin (S-opsin) in rods and also lacking chromophore to exploit the fact that cone opsins, but not R-opsin, require chromophore for proper folding and trafficking to the photoreceptor's outer segment. In R-opsin's absence, S-opsin in these transgenic rods without chromophore was mislocalized; in R-opsin's presence, however, S-opsin trafficked normally to the rod outer segment and produced functional S-pigment upon subsequent chromophore restoration. Introducing a competing R-opsin transmembrane helix H1 or helix H8 peptide, but not helix H4 or helix H5 peptide, into these transgenic rods caused mislocalization of R-opsin and S-opsin to the perinuclear endoplasmic reticulum. Importantly, a similar peptide-competition effect was observed even in WT rods. Our work provides convincing evidence for visual pigment dimerization in vivo under physiological conditions and for its role in pigment maturation and targeting. Our work raises new questions regarding a potential mechanistic role of dimerization in rhodopsin signaling.