Journal Article

Structural mechanism for nucleotide-driven remodeling of the AAA-ATPase unfoldase in the activated human 26S proteasome

Zhu, Yanan, Lu, Ying, Ouyang, Qi, Wang, Wei Li, Yu, Daqi, Mao, Youdong

2018

Overview

The proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all known eukaryotic cells. It remains elusive how conformational changes of the AAA-ATPase unfoldase in the regulatory particle (RP) control the gating of the substrate–translocation channel leading to the proteolytic chamber of the core particle (CP). Here we report three alternative states of the ATP-γ-S-bound human proteasome, in which the CP gates are asymmetrically open, visualized by cryo-EM at near-atomic resolutions. At least four nucleotides are bound to the AAA-ATPase ring in these open-gate states. Variation in nucleotide binding gives rise to an axial movement of the pore loops narrowing the substrate-translation channel, which exhibit remarkable structural transitions between the spiral-staircase and saddle-shaped-circle topologies. Gate opening in the CP is thus regulated by nucleotide-driven conformational changes of the AAA-ATPase unfoldase. These findings demonstrate an elegant mechanism of allosteric coordination among sub-machines within the human proteasome holoenzyme. The 26S proteasome consists of a core particle that is capped at each side by a regulatory particle. Here the authors present cryo-EM structures of the activated human 26S proteasome holoenzyme in three alternative open-gate states, which provides mechanistic insights into gate opening and dynamic remodeling of the substrate–translocation pathway.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 119/118 / 147/143 / 631/45/468 / 631/535/1258/1259 / 82/16 / 82/83 / Adenosine triphosphatase / Adenosine Triphosphatases - chemistry / Adenosine Triphosphatases - genetics / Adenosine Triphosphatases - metabolism / Adenosine triphosphate / Adenosine Triphosphate - analogs & derivatives / Adenosine Triphosphate - chemistry / Adenosine Triphosphate - metabolism / Allosteric properties / Allosteric Regulation / Amino Acid Sequence / Arabidopsis Proteins - chemistry / Arabidopsis Proteins - genetics / Arabidopsis Proteins - metabolism / ATPases Associated with Diverse Cellular Activities - chemistry / ATPases Associated with Diverse Cellular Activities - genetics / ATPases Associated with Diverse Cellular Activities - metabolism / Binding Sites / Biodegradation / Biology / Cancer / Cell division / Channel gating / Core particles / Cryoelectron Microscopy / Datasets / Gene expression / Holoenzymes - chemistry / Holoenzymes - genetics / Holoenzymes - metabolism / Humanities and Social Sciences / Humans / Kinetics / Models, Molecular / multidisciplinary / Nucleotides / Nucleotides - chemistry / Nucleotides - metabolism / Physics / Proteasome 26S / Proteasome Endopeptidase Complex - chemistry / Proteasome Endopeptidase Complex - genetics / Proteasome Endopeptidase Complex - metabolism / Protein Binding / Protein Conformation, alpha-Helical / Protein Conformation, beta-Strand / Protein Interaction Domains and Motifs / Proteolysis / Saccharomyces cerevisiae Proteins - chemistry / Saccharomyces cerevisiae Proteins - genetics / Saccharomyces cerevisiae Proteins - metabolism / Science / Science (multidisciplinary) / Sequence Alignment / Sequence Homology, Amino Acid / Substrates / Translocation