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

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 4; p. 629
• Main Authors: Zhang, Shuwen, Mao, Youdong
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.04.2020; MDPI
• Subjects: 26S proteasome; AAA+ ATPase; Adenosine; Adenosine triphosphatase; Adenosine Triphosphate - metabolism; ATP-dependent proteolysis; ATPases Associated with Diverse Cellular Activities - chemistry; ATPases Associated with Diverse Cellular Activities - metabolism; Cdc48/p97; Cell cycle; Electron microscopy; Gene expression; Hexamers; Humans; Mitochondria; mitochondrial protease; Models, Molecular; Proteasome 26S; Protein Domains; Proteins; Proteolysis; Review; Sensors; Signal transduction; Structure-function relationships; Substrate Specificity; substrate translocation; 26S proteasome; ATP-dependent proteolysis; Cdc48/p97; AAA+ ATPase; substrate translocation; mitochondrial protease
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10040629

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.