The First Residue of the PWWP Motif Modulates HATH Domain Binding, Stability, and Protein–Protein Interaction
Copyright policy )The First Residue of the PWWP Motif Modulates HATH Domain Binding, Stability, and Protein–Protein Interaction
Hepatoma-derived growth factor (hHDGF) and HDGF-related proteins (HRPs) contain conserved N-terminal HATH domains with a characteristic structural motif, namely the PWWP motif. The HATH domain has attracted attention because of its ability to bind with heparin/heparan sulfate, DNA, and methylated histone peptide. Depending on the sequence of the PWWP motif, HRP HATHs are classified into P-type (Pro-His-Trp-Pro) and A-type (Ala-His-Trp-Pro) forms. A-type HATH is highly unstable and tends to precipitate in solution. We replaced the Pro residue in P-type HATHHDGF with Ala and evaluated the influence on structure, dynamics, and ligand binding. Nuclear magnetic resonance (NMR) hydrogen/deuterium exchange and circular dichroism (CD) measurements revealed reduced stability. Analysis of NMR backbone (15)N relaxations (R1, R2, and nuclear Overhauser effect) revealed additional backbone dynamics in the interface between the β-barrel and the C-terminal helix bundle. The β1-β2 loop, where the AHWP sequence is located, has great structural flexibility, which aids HATH-HATH interaction through the loop. A-type HATH, therefore, shows a stronger tendency to aggregate when binding with heparin and DNA oligomers. This study defines the role of the first residue of the PWWP motif in modulating HATH domain stability and oligomer formation in binding.
- National Chiao Tung University Taiwan
- University System of Taiwan Taiwan
- Kaohsiung Medical University Taiwan
- National Tsing Hua University Taiwan
Models, Molecular, Heparin, Protein Conformation, Protein Stability, Molecular Sequence Data, DNA, Humans, Intercellular Signaling Peptides and Proteins, Protein Interaction Domains and Motifs, Amino Acid Sequence, Sequence Alignment, Protein Binding
Models, Molecular, Heparin, Protein Conformation, Protein Stability, Molecular Sequence Data, DNA, Humans, Intercellular Signaling Peptides and Proteins, Protein Interaction Domains and Motifs, Amino Acid Sequence, Sequence Alignment, Protein Binding
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).6 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average
Citations provided by BIP!Popularity provided by BIP!