A Mechanistic Perspective on PEX1 and PEX6, Two AAA+ Proteins of the Peroxisomal Protein Import Machinery.

Ana G Pedrosa,Tânia Francisco,Jorge E Azevedo,Aurora Barros-Barbosa,Maria J Ferreira,Tony A Rodrigues

doi:10.3390/ijms20215246

Ana G Pedrosa, Tânia Francisco + Show 4 more

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https://doi.org/10.3390/ijms20215246

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Abstract

In contrast to many protein translocases that use ATP or GTP hydrolysis as the driving force to transport proteins across biological membranes, the peroxisomal matrix protein import machinery relies on a regulated self-assembly mechanism for this purpose and uses ATP hydrolysis only to reset its components. The ATP-dependent protein complex in charge of resetting this machinery—the Receptor Export Module (REM)—comprises two members of the “ATPases Associated with diverse cellular Activities” (AAA+) family, PEX1 and PEX6, and a membrane protein that anchors the ATPases to the organelle membrane. In recent years, a large amount of data on the structure/function of the REM complex has become available. Here, we discuss the main findings and their mechanistic implications.

Highlights

Many newly synthesized proteins have to be translocated across at least one biological membrane in order to reach their final destination
PEX1 and PEX6 turned out to be members of the large family of ATPases Associated with diverse cellular Activities (AAA+), and the only proteins involved in peroxisomal matrix protein import possessing ATP binding/hydrolysis domains [95,96]
This finding, together with previous experiments showing that the overall process of peroxisomal protein import requires ATP hydrolysis [97,98,99,100,101] led to initial models proposing that PEX1 and PEX6 might participate at a pre-translocation step, or in the vectorial transport of proteins across the organelle membrane, or in the assembly of the Docking/Translocation Module (DTM)

Summary

Introduction

Many newly synthesized proteins have to be translocated across at least one biological membrane in order to reach their final destination. Translocation directionality is attained through strong molecular interactions established between components of the translocation machinery which end up pushing the substrate across the membrane (regulated self-assembly mechanisms; e.g., peroxisomal matrix protein import, type V and VI bacterial secretion systems, and AB-type toxins; [3,5,12]) In some of the latter cases energy from ATP hydrolysis is still needed but only to reset the protein translocation machinery [13]. After delivery of the cargo, the “syringe” is disassembled, i.e., the “plunger” is extracted from the “barrel” so that a new cycle of protein transportation can be started This is the only part of the pathway where energy from ATP hydrolysis is required The available structural/functional data on the REM are discussed below

The Receptor Export Module—the Initial Findings

The Mechanism of the Receptor Export Module

Unsolved Mechanistic Aspects

The Energetic Cost of Protein Translocation across the Peroxisomal Membrane

Findings

Conclusions