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A Landmark Research on Human Proteasome for Pathogenesis of Multiple Myeloma and Neurodegenerative Diseases


A Landmark Research on Human Proteasome for Pathogenesis of Multiple Myeloma and Neurodegenerative Diseases
New York, NY, November 19, 2018 --(PR.com)-- A team of researchers from Dana-Farber Cancer Institute, Harvard Medical School (Boston, USA) and Peking University (Beijing, China) led by Dr. Youdong Mao have brought about a landmark research that provides the sharpest 3D “motion picture” of human 26S proteasome functioning in atomic detail, and significantly advances understanding and knowledge about how the human proteasome machinery degrades a protein substrate. This study opens up numerous possibilities for structure-based drug discovery targeting human proteasome for treatment of multiple myeloma and neurodegenerative diseases.

In eukaryotic cells, proteasomes are the largest, most important protein complex machines that degrade damaged proteins using proteolysis, a chemical reaction that breaks peptide bonds. Proteins are tagged for degradation with a small protein called ubiquitin. Proteasomes are part of a major mechanism called Ubiquitin Proteasome Pathway (UPP), by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The UPP mechanism maintains the balance of cellular protein contents and regulates myriad cellular processes, such as cell cycle, apoptosis, immune response, inflammation, and the response to proteotoxic stress. The 26S proteasome holoenzyme recognizes and processes poly-ubiquitinated substrates. This holoenzyme is assembled from a barrel-shaped, proteolytically active core particle and two 19S regulatory particles, capping both ends of the core particle cylinder. The proteasome regulatory particle consists of the lid and base sub-complexes. Once substrate is captured by the regulatory particle, its globular domains are mechanically unfolded by adenosine triphosphatase (ATPase) motor module. The ATPase motor module regulates the engagement deubiquitylation and degradation of substrates through previously unknown mechanisms.

Cryo-electron microscopy or Cyro-EM is a technique used for determining high-resolution structure of biomolecules. In past researches, cryo-electron microscopy analysis has revealed the architecture of the substrate-free proteasome holoenzyme in six distinct states. In the study reported in Nature, The International Journal of Science on November 12, 2018 (https://www.nature.com/articles/s41586-018-0736-4), Youdong Mao et al. have successfully decoded the atomic structures of the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 Å resolution, captured during breakdown of a polyubiquitylated protein. This research sheds lights on mechanisms by which the substrate is engaged, de-ubiquitylated, unfolded, and translocated by the human proteasome. It reveals for the first time how ATP hydrolysis regulates the engagement, deubiquitylation and degradation of substrates through three principal modes of coordinated actions.

The research team used model substrate Sic1PY and a novel nucleotide-substitution strategy to image the human proteasome in the action of substrate processing. The team determined cryo-EM structures of the substrate-engaged proteasome in seven distinct conformational states, designated as EA1, EA2, EB, EC1, EC2, ED1 and ED2, to nominal resolutions of 2.8-3.6 Å. The team observed that the key structural features of the seven states demonstrated remarkable spatiotemporal continuity in substrate binding and nucleotide states. In this study, structural comparison of states EA and EB explains how ATP hydrolysis regulates substrate engagement for deubiquitylation. States EC1 and EC2 present two successive conformations that are compatible with the initiation of substrate translocation, whereas states ED1 and ED2 capture two consecutive conformations of processive substrate translocation. Structural comparison of ED1 and ED2 provides insight into the mechanism of substrate unfolding and translocation. The study also discusses the long-range quaternary allosteric regulation associated with and very specific to states ED1 and ED2. Through analysis and observations of these seven native states, the authors conclude that these seven states are on the pathway of substrate processing by the holoenzyme.

The authors found that the initiation of substrate translocation is extensively coordinated with other regulatory events preparing the proteasome for processive substrate degradation. Through further systematic analysis, the team discovered how the chemical energy of ATP hydrolysis is converted into the mechanical work of substrate unfolding through a highly concerted process.

This research provides novel insights into the complete cycle of substrate processing by unravelling the distinct modes followed by ATP hydrolysis in the proteasome holoenzyme. The researchers observed three principal modes of coordinated hydrolysis, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases, and in one ATPase at a time. These hydrolytic modes regulate deubiquitylation, translocation initiation, and processive unfolding of substrates, respectively.

The authors noted certain limitations in this study that the multiplicity of nucleotide processing events in distinct ATPases, during transitions between consecutive states of the proteasome, may have resulted in the absence of fast steps and sparsely populated intermediate states in their cryo-EM reconstructions. The team envisions the prospect of further explorations in this regard, by identifying these missing intermediaries to clarify how ATP hydrolytic events and nucleotide exchange are coordinated with each other, and allosterically linked to substrate translocation.

This research by Youdong Mao et al. reveals a plethora of potential substrate-binding sites that can facilitate future development of drugs that modulate proteasome functions implicated in various diseases, such as multiple myeloma and neurodegenerative diseases. The atomic structures of the human proteasome explored in this research provide a blueprint for future researches in pursuit of further understanding UPP and developing molecular medicine for various cancers and diseases.
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