"Nature": Zhao Minglei/Liu Lei team reveals the key mechanism of protein degradation

For the thousands of lives in nature, protein synthesis forms the basis of all life activities

The so-called ubiquitination refers to a protein modification process: with the participation of a series of enzymes, ubiquitin molecules select specific target proteins and "label" them

It has now been discovered that this modification process, which is widespread in eukaryotes, regulates almost all cellular processes, including cell division, DNA repair, and immune response

This week, in a new study published in Nature, the team of Professor Minglei Zhao from the University of Chicago and the team of Professor Lei Liu from Tsinghua University used protein chemical synthesis technology and cryo-electron microscopy to deeply explore the specific mechanism of ubiquitination.

Among the enzymes involved in ubiquitination modification, ubiquitin ligase (E3 enzyme) is essential for the formation of ubiquitination

The N-terminal degradation pathway determines the degradation rate of most proteins in the human body, and errors in this pathway will lead to the accumulation of misfolded or damaged proteins, which will further lead to the aging process, neurodegenerative diseases, and some rare autosomal recessive inheritance.

However, even though Ubr1 has been discovered for more than 30 years, how it initiates ubiquitination and how the K48 chain ubiquitin chain extends is still unknown

In this study, the research team first used protein chemical synthesis technology to simulate the intermediates in the Ubr1 catalytic reaction

▲Schematic diagram of Ubr1 opening the ubiquitination reaction (picture source: Pan, et al, University of Chicago)

Based on these studies, the research team also clarified a series of key structural elements for Ubr1 to catalyze the ubiquitination reaction, thereby helping us to further understand the reaction mechanism of protein polyubiquitination mediated by E3 enzyme

Professor Minglei Zhao, the co-corresponding author of the paper, said: “Before this research, we had very limited understanding of how ubiquitin polymers are formed

Professor Minglei Zhao from the University of Chicago, Professor Lei Liu from Tsinghua University, and Dr.

Reference materials:

[1] Pan, M.

[2] Advanced microscopes help scientists understand how cells break down proteins.