A New groundbreaking research may fight cancers and neurodegenerative diseases

November 16 23:05 2018

Youdong Mao has made a landmark research on “Cryo-EM structures and dynamics of the substrate-engaged human 26S proteasome (https://www.nature.com/articles/s41586-018-0736-4)”. This research article was published with Nature, the International journal of science. https://doi.org/10.1038/s41586-018-0736-4.

Mao conceived and supervised this study, devised the methods, performed atomic modeling, analyzed the structures and wrote the manuscript.

Cryoelectron microscopy (Cryo-EM) is a technology for imaging frozen-hydrated specimens at cryogenic temperatures by electron microscopy. Specimens remain in their native state without the need for dyes or fixatives, allowing the study of fine cellular structures, viruses and protein complexes at molecular resolution. The proteasome is an ATP-dependent, 2.5-megadalton machine responsible for selective protein degradation in eukaryotic cells.

Mao and the team presented cryo-EM structures of the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 Å resolution, captured during a breakdown of a polyubiquitylated protein. Although cryo-EM has been used to elucidate atomic structures of stable proteins in a resting, equilibrium state, this is the first time that it was successfully used to analyze atomic-level dynamics of a megadalton protein machinery in nonequilibrium states during the course of its action with a substrate at 3.6-Å or higher resolution.

As the team wanted to capture the human proteasome in the action of substrate processing, they used the model substrate Sic1PY and developed a novel nucleotide-substitution strategy.

The team analyzed an unprecedentedly large number of cryo-EM data, 44664 micrographs of 8k-by-8k size. The resulting seven structures demonstrate remarkable spatiotemporal continuity and visualize a continuum of dynamic substrate-proteasome interactions from ubiquitin recognition to deubiquitylation and to substrate translocation. During the course of their research, they observed that ATP hydrolysis sequentially navigated through all six ATPases, a first-time, significant achievement made possible for any ATPase hexamers in any species.

On further examination, three principal modes of coordinated hydrolysis were surprisingly observed, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases, and in one ATPase at a time.

It was seen that these hydrolytic modes regulated deubiquitylation, translocation initiation and processive unfolding of substrates, respectively.

In addition to the above findings, Mao and the team pinpointed how ATP hydrolysis powered a hinge-like motion in each ATPase that regulated its substrate interaction.

They found that synchronization of ATP binding, ADP release and ATP hydrolysis in three adjacent ATPases drives rigid-body rotations of substrate-bound ATPases that are propagated unidirectionally in the ATPase ring and help to unfold the substrate.

Furthermore, during transitions between consecutive states of the proteasome, the multiplicity of nucleotide processing events in distinct ATPases implied that fast steps and sparsely populated intermediate states might have been missed in their cryo-EM reconstructions.

Further studies conducted by Mao and his team, which will identify the missing intermediaries, would be required to clarify how ATP hydrolytic events and nucleotide exchange are coordinated with each other and allosterically linked to substrate translocation.

Finally, Mao and the team arrived at a conclusion. They determined the atomic structures of the substrate-engaged human proteasome in seven native states during degradation of a polyubiquitylated substrate, which together characterizes the atomic-level dynamics of substrate-proteasome interactions during the complete cycle of substrate processing for the first time.

They realized that the structures provided a wealth of atomic-level information accounting for several decades of biochemical studies of proteasome function.

According to the team of researchers, a plethora of substrate-binding sites was revealed in the study carried out by them. This research will further facilitate the future development of drugs that modulate proteasome functions implicated in various diseases, such as cancers and neurodegenerative diseases. Regulating protein degradation through human proteasome system is a highly attractive strategy to combat cancers and other diseases as it allows targeted removal of redundant proteins required for the progression of tumors or upregulation of proteins suppressing such a progression.

This can be a breakthrough research to understand the basis of various diseases like multiple myeloma, a blood cancer related to lymphoma, which can’t usually be cured and neurodegenerative diseases, a heterogeneous group of disorders.  These are characterized by the progressive degeneration of the structures and function of the central nervous system or peripheral nervous system. Common neurodegenerative diseases include Alzheimer’s disease and Parkinson’s disease.

Youdong Mao’s study has opened new doors in the medical field. It will act as a base for young researchers who can make further advancements in this research, which will eventually aid in the treatment of cancers and neurodegenerative diseases.

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