Shin-biology regulated by protein lifetime

Grant-in-Aid for Transformative Research Areas (A) FY2023–FY2027, MEXT Japan

Planned Research

Mechanism of how the proteasome determines protein lifetime
Yasushi Saeki
Division of Protein Metabolism, The Institute of Medical Science, The University of Tokyo

The proteasome determines the lifespan of a wide range of proteins by timely and selective proteolysis, but the detailed molecular mechanisms of this process remain still elusive, particularly the molecular details that identify the structural diversity of ubiquitin modifications and substrate degrons. We have found that several shuttle molecules that transport ubiquitylated substrates to the proteasome, as well as the ubiquitin-selective ATPase p97, play crucial roles in proteasomal degradation, and that under stress the shuttle molecules undergo liquid-liquid phase separation with the ubiquitylated substrates to form proteasome condensates. In this planned research, we will expand our knowledge of the molecular mechanism of substrate selection after the ubiquitylation step and the spatio-temporal control of proteasomal degradation using large-scale protein lifetime measurements and targeted protein degradation methods developed in this research area. Then, we will extract common features of proteasome substrates and essential elements for proteasomal degradation by informational analysis, and further evaluate them in cells to understand the underlying principle of the regulation of protein lifetime by proteasomes.

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