Atomic resolution Cryo-EM structure of human proteasome activator PA28γ.

The PA28 family proteasome activators play important roles in regulating proteasome activities. Though the three paralogs (PA28α, PA28ß, and PA28γ) are similar in terms of primary sequence, they show significant differences in expression pattern, cellular localization and most importantly, biological functions. While PA28αß is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28γ is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. However, why this paralog has the unique function remains elusive. Previous structural studies have mainly focused on mammalian PA28α, PA28ß and PA28αß heptamers, while structural studies on mammalian PA28γ of atomic resolution are still absent to date. In the present work, we determined the Cryo-EM structure of the human PA28γ heptamer at atomic resolution, revealing interesting unique structural features that may hint our understanding the functional mechanisms of this proteasome activator.

Effect of tocopheryl polyethylene glycol succinate on the percutaneous penetration of minoxidil from water/ethanol/polyethylene glycol 400 solutions.

We described to achieve the local retention of minoxidil which has penetrated the skin with minimization of its absorption into the general circulation and elimination of local irritation induced by propylene glycol. The effect of tocopheryl polyethylene glycol succinate (TPGS) on the penetration flux of minoxidil and its retention in the skin from topical minoxidil formulations consisting of water, alcohol, and polyethylene glycol 400 was characterized by an experimental design of ten solvent formulations in this study. Results show that the addition of TPGS was only able to improve the solubility of minoxidil in those solvent systems containing higher proportions of water and PEG 400, and the extent of improvement was also more profound with the addition of TPGS at concentrations higher than 5%. For those solvent systems containing a higher fraction of alcohol, an insignificant change in minoxidil solubility with increasing added amounts of TPGS was noted even with the tendency to decrease the solubility of minoxidil with higher amounts of TPGS. Increasing the amount of TPGS added gradually increased the flux and the corrected flux from solvent formulations with a lower solubility parameter, but decreased those from solvent systems with a higher solubility parameter. With the addition of TPGS, solvent formulation F6 (alcohol:PEG 400 of 50:50) was demonstrated to be the optimal choice by having an improved local effect and a reduced systemic effect compared to the reference of 2% Regaine((R)). Tocopheryl polyethylene glycol succinate (TPGS) was mainly retained locally in the stratum corneum, and the amount was proportional to the increase in the amount of TPGS added to these ten solvent formulations.