pH Dependence of HSF1 trimerization is shaped by intramolecular interactions

• Published in: Biochemical and biophysical research communications 2024-05, Vol.709, p.149824, Article 149824
• Main Authors: Choi, Bo-Hee, Lee, Chang-Ju, Kim, Tae Hwan, Kim, David Nahm-Joon, Park, Young-Shang, Choi, Jeong-Mo, Park, Jang-Su
• Format: Article
• Language: English
• Subjects: DNA-Binding Proteins - metabolism; Heat Shock Transcription Factors - genetics; Histidine; Histidine - genetics; Histidine - metabolism; HSF1; Humans; Hydrogen-Ion Concentration; Protonation; Transcription Factors - metabolism; Trimerization; Tyrosine
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.149824

Heat shock factor 1 (HSF1) primarily regulates various cellular stress responses. Previous studies have shown that low pH within the physiological range directly activates HSF1 function in vitro. However, the detailed molecular mechanisms remain unclear. This study proposes a molecular mechanism based on the trimerization behavior of HSF1 at different pH values. Extensive mutagenesis of human and goldfish HSF1 revealed that the optimal pH for trimerization depended on the identity of residue 103. In particular, when residue 103 was occupied by tyrosine, a significant increase in the optimal pH was observed, regardless of the rest of the sequence. This behavior can be explained by the protonation state of the neighboring histidine residues, His101 and His110. Residue 103 plays a key role in trimerization by forming disulfide or non-covalent bonds with Cys36. If tyrosine resides at residue 103 in an acidic environment, its electrostatic interactions with positively charged histidine residues prevent effective trimerization. His101 and His110 are neutralized at a higher pH, which releases Tyr103 to interact with Cys36 and drives the effective trimerization of HSF1. This study showed that the protonation state of a histidine residue can regulate the intramolecular interactions, which consequently leads to a drastic change in the oligomerization behavior of the entire protein. •Inter-chain interactions of key residues are crucial for HSF1 DBD trimerization.•In one ortholog, the key residue is tyrosine surrounded by histidine residues.•PH can alter the charge state of histidine and its interactions with tyrosine.•The identity of the key residue governs pH dependence of HSF1 DBD trimerization.