AP-3 shows off its flexibility for the cryo-EM camera

Todd R Graham

doi:10.1016/j.jbc.2021.101491

Abstract

The tetrameric adaptor protein AP-3 is critical for the transport of proteins to lysosomes and lysosome-related organelles. The structures of homologous adaptors AP-1 and AP-2 have revealed a closed-to-open conformational change upon membrane recruitment and phosphoinositide binding. Recently, Schoppe et al. reported the first cryo-EM structures of AP-3 from budding yeast and described remarkably flexible solution structures that are all in the open conformation. The apparent lack of a closed conformational state, the first such description in the literature, allows AP-3 to be more reliant on cargo interaction for its initial membrane recruitment compared with AP-1.

Highlights

The role AP-3 plays in protein trafficking was illuminated through the characterization of mutations causing changes in eye color in Drosophila, coat color in mice, and mislocalization of alkaline phosphatase in yeast [3]
AP-2 is recruited from the cytosol to the plasma membrane by binding phosphatidylinositol-4,5-bisphosphate and sorting signals, whereas AP-1 is recruited to the trans-Golgi network by binding to PI4P, Arf-GTP, and sorting signals present in integral membrane cargo proteins [2, 7, 8]
Arf-GTP and/or phosphoinositide interactions induce a conformational change to an open state that swings the μ subunit into a position that allows cargo engagement (Fig. 1)

Summary

Introduction

The role AP-3 plays in protein trafficking was illuminated through the characterization of mutations causing changes in eye color in Drosophila (garnet), coat color in mice (mocha, pearl), and mislocalization of alkaline phosphatase in yeast [3]. All of the tetrameric adaptors recognize similar YXXΦ and dileucine sorting signals in cargo proteins and, must have other binding interactions that confer organelle-specific membrane recruitment [1]. AP-1, AP-3, and AP-4 all require the small GTP-binding protein ADP-ribosylation factor (ARF) in its GTP-bound form for recruitment to Golgi or endosomal membranes.

Results

Conclusion