Journal
CELL CHEMICAL BIOLOGY
Volume 28, Issue 5, Pages 722-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2021.01.007
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Funding
- Research Grants Council of Hong Kong [17309616, C7017-18G]
- National Science Foundation of China [21672180, 91753101]
- Area of Excellence Scheme of the University Grants Committee of Hong Kong [AoE/P-705/16]
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This study investigated the impact of phosphorylation on HMGA1a, a member of intrinsically disordered proteins, revealing its role in inhibiting protein-protein interaction and inducing conformational changes. Through chemical synthesis and mass spectrometry, it was shown that phosphorylation in non-protein-binding domains can regulate the conformation and function of IDPs.
As a typical member of intrinsically disordered proteins (IDPs), HMGA1a carries many post-translational modifications (PTMs). To study the undefined function of acidic tail phosphorylations, seven HMGA1a proteins with site-specific modification(s) were chemically synthesized via Ser/Thr ligation. We found that the phosphorylations significantly inhibit HMGA1a-P53 interaction and the phosphorylations can induce conformational change of HMGA1a from an open state'' to a close state.'' Notably, the positively charged lysinearginine (KR) clusters are responsible formodulating HMGA1a conformation via electrostatic interaction with the phosphorylated acidic tail. Finally, we used a synthetic protein-affinity purification mass spectrometry (SP-AP-MS) methodology to profile the specific interactors, which further supported the function of HMGA1a phosphorylation. Collectively, this study highlights a mechanismfor regulating IDPs' conformation and function by phosphorylation of non-protein-binding domain and showcases that the protein chemical synthesis in combination with mass spectrometry can serve as an efficient tool to study the IDPs' PTMs.
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