title: Structural Insights into the Allosteric Operation of the Lon AAA+ Protease.
abstract: The Lon AAA+ protease (LonA) is an evolutionarily conserved protease that couples the ATPase cycle into motion to drive substrate translocation and degradation. A hallmark feature shared by AAA+ proteases is the stimulation of ATPase activity by substrates. Here we report the structure of LonA bound to three ADPs, revealing the first AAA+ protease assembly where the six protomers are arranged alternately in nucleotide-free and bound states. Nucleotide binding induces large coordinated movements of conserved pore loops from two pairs of three non-adjacent protomers and shuttling of the proteolytic groove between the ATPase site and a previously unknown Arg paddle. Structural and biochemical evidence supports the roles of the substrate-bound proteolytic groove in allosteric stimulation of ATPase activity and the conserved Arg paddle in driving substrate degradation. Altogether, this work provides a molecular framework for understanding how ATP-dependent chemomechanical movements drive allosteric processes for substrate degradation in a major protein-destruction machine.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 11529, ROC; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan 30013, ROC.
authors.forename: Chien-Chu
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 11529, ROC; Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan 10617, ROC.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Su
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 11529, ROC.
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Su
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan 10051, ROC.
authors.forename: Pi-Hui
authors.initials: PH
authors.lastname: Liang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 11529, ROC.
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Feng
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 11529, ROC; Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan 10617, ROC.
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 11529, ROC; Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan 10617, ROC. Electronic address: chungi@gate.sinica.edu.tw.
authors.forename: Chung-I
authors.initials: CI
authors.lastname: Chang
mesh_terms: D049069:ATP-Dependent Proteases / Q000737:chemistry* / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation
chemical_list: D024101:Mitochondrial Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D049069:ATP-Dependent Proteases; C000595973:LONP1 protein, human
keywords: AAA+ protease; ATPase cycle; LonA; allosteric regulation; crystal structure; pore loops; protein degradation; translocation