AAA+ ATPases in Protein Degradation: Structures, Functions and Mechanisms.

Shuwen Zhang,Youdong Mao

doi:10.3390/biom10040629

Shuwen Zhang, Youdong Mao

Open Access

https://doi.org/10.3390/biom10040629

Copy DOI

Abstract

Adenosine triphosphatases (ATPases) associated with a variety of cellular activities (AAA+), the hexameric ring-shaped motor complexes located in all ATP-driven proteolytic machines, are involved in many cellular processes. Powered by cycles of ATP binding and hydrolysis, conformational changes in AAA+ ATPases can generate mechanical work that unfolds a substrate protein inside the central axial channel of ATPase ring for degradation. Three-dimensional visualizations of several AAA+ ATPase complexes in the act of substrate processing for protein degradation have been resolved at the atomic level thanks to recent technical advances in cryogenic electron microscopy (cryo-EM). Here, we summarize the resulting advances in structural and biochemical studies of AAA+ proteases in the process of proteolysis reactions, with an emphasis on cryo-EM structural analyses of the 26S proteasome, Cdc48/p97 and FtsH-like mitochondrial proteases. These studies reveal three highly conserved patterns in the structure–function relationship of AAA+ ATPase hexamers that were observed in the human 26S proteasome, thus suggesting common dynamic models of mechanochemical coupling during force generation and substrate translocation.

Highlights

Protein degradation plays a fundamental role in the maintenance of cellular homeostasis and the regulation of most major cellular processes, such as cell cycle regulation, gene expression, signal transduction, immune response, apoptosis and carcinogenesis [1]
Understanding the structures and functions of these key protease complexes and their implications in pathological conditions is instrumental for therapeutic development
The globular domains of these proteins have to be unfolded and delivered to the proteolytically active sites before they can be broken down into short polypeptides. This sophisticated task is thought to be carried out by protease complexes containing ring-like structures assembled from adenosine triphosphatase (ATPase) of the ATPases associated with a variety of cellular activities (AAA+) superfamily that is essential for most proteolytic activities [8,9]

Summary

Introduction

Protein degradation plays a fundamental role in the maintenance of cellular homeostasis and the regulation of most major cellular processes, such as cell cycle regulation, gene expression, signal transduction, immune response, apoptosis and carcinogenesis [1]. The globular domains of these proteins have to be unfolded and delivered to the proteolytically active sites before they can be broken down into short polypeptides This sophisticated task is thought to be carried out by protease complexes containing ring-like structures assembled from adenosine triphosphatase (ATPase) of the ATPases associated with a variety of cellular activities (AAA+) superfamily that is essential for most proteolytic activities [8,9]. In addition to an N-terminal (N) domain and a flexible C-terminal tail, a Cdc monomer encompasses two tandem ATPase domains (D1 and D2), each forming a ring-like homohexamer in the complex (Figure 1a,c) Both D1 and D2 are homologous to the single AAA domain of proteasome-activating nucleotidase (PAN) and proteasomal RPT subunits, hosting a nucleotide-binding pocket and pore-1/2 loops that can interact with substrates [17,18,19,20,21,22,98]. It can either form a homohexamer of AFG3L2 subunits or a heterohexamer of alternating AFG3L2 and paraplegin (SPG7) subunits [113,114], whereas in yeast it is an obligate heterohexamer of alternating Yta and Yta subunits [115]

Conformational Changes of AAA ATPases in the 26S Proteasome

How Are Substrate Interactions Coupled with ATP Hydrolysis?

How Is the Cycling of ATP Hydrolysis Coordinated for Functional Regulation?

Is There Real Evidence for a Sequential Model of Coordinated ATP Hydrolysis?