Mao Youdong's team "Nature" published a breakthrough technology to crack the key mechanism of protein degradation

A new paper by a research team from Peking University has been published online in the journal Nature

The research team pointed out that, as a biological molecular machine that affects the degradation of proteins in cells, the proteasome is a drug target for the treatment of a series of major diseases.

In eukaryotic cells, including human cells, the ubiquitin-protease system is a major means of directed degradation of proteins

Focusing on the proteasome, Prof.

In normal cells, the function of the proteasome is tightly regulated at multiple levels

However, this process is extremely fast, and the time scale of proteasome degradation of substrates is between milliseconds and seconds, so it is always a world-class problem to understand how USP14 is activated by the proteasome and regulates proteasome function

And this is where the breakthrough of this study lies: the conformational continuum of USP14 and the proteasome during protein degradation is presented at the atomic level

▲ One of the atomic structural models of the degradation of polyubiquitinated substrates by the proteasome complex under the regulation of USP14 (A), time-resolution cryo-EM analysis of the temporal evolution of the statistical distribution of the 13 intermediate states with the process of protein degradation (B) (picture Source: Professor Mao Youdong/CC BY 4.

In order to capture the intermediate state structure of the process with cryo-EM, the research team first managed to slow down the process

Next, a more critical step is to classify such a large number of images, showing the dynamic process of the protein response

▲The parallel pathway model of USP14-regulated proteasomal substrate degradation obtained by time-resolved cryo-electron microscopy analysis (Image credit: Prof.

Combined with molecular biological function and gene mutation studies, this work finally elucidates the atomic structural basis and non-equilibrium kinetic mechanism of the reciprocal regulatory activities of USP14 and 26S proteasome

It was found that the activation of USP14 is dependent on both ubiquitin recognition and the binding of the proteasome RPT1 subunit

In the review article published at the same time in "Nature", the reviewer has a high evaluation of the study, pointing out that "this work is a major study that finally solves the problem of USP14 activation and its mechanism of regulating proteasome function at the atomic level"

Note: The original text has been deleted

References:

[1] Shuwen Zhang et al.

[2] Control of human protein-degradation machinery revealed.