Dissection of the relationship between folding stability and biological lifetime of proteins

Project: Research project

Project Details

Description

Protein degradation systems maintain protein homeostasis. A failure of these systems causes various
diseases, such as neurodegenerative diseases and cancers. In eukaryotic cells, ubiquitin is a general
marker for selective degradation and determines protein lifetime in vivo. In selective degradation, E3
ubiquitin ligases determine target proteins. Although there are ~800 E3 ligases in human, only a
handful of them have already shown to recognize specific short peptide motifs called “degrons”.
Moreover, the feature(s) for unstable or misfolded structures recognized by E3 ligases remain unclear.
In part, this is because we lack a comprehensive approach to investigate the global relationship
between protein structural stability, ubiquitination status, and lifetime of the protein.
To reveal the effect of protein folding stability (and other features) on ubiquitination and biological
lifetime in vivo, I propose to measure these parameters for thousands of designed mini-proteins,
whose folding stability has been previously characterized in detail. First, I will measure biological
lifetime for these mini-proteins by flow cytometry, and monitor their ubiquitination status by using
top-down proteomics approach. Then, I will analyze these data by using in silico analysis and decipher
what factor(s) determine ubiquitination states and biological lifetime. This highly innovative and
comprehensive approach using thousands of designed proteins will allow me to uncover the
fundamental principle for protein lifetime in vivo and provide a mechanistic basis for designing better
tools to manipulate protein lifetime.
StatusActive
Effective start/end date3/31/213/30/24

Funding

  • International Human Frontier Science Program Organization (LT000166/2020)

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