The First Residue of the PWWP Motif Modulates HATH Domain Binding, Stability, and Protein–Protein Interaction
| Autor: | Yi Lin Hung, Wei-Cheng Lo, Hsia Ju Lee, Ingjye Jiang, Shang Chi Lin, Yi Jan Lin, Shih Che Sue |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Helix bundle Circular dichroism Heparin Protein Conformation Protein Stability Chemistry Molecular Sequence Data DNA Nuclear Overhauser effect Plasma protein binding Biochemistry Protein–protein interaction Crystallography Protein structure Humans Intercellular Signaling Peptides and Proteins Protein Interaction Domains and Motifs Amino Acid Sequence Structural motif Sequence Alignment Peptide sequence Protein Binding |
| Zdroj: | Biochemistry. 54:4063-4074 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/acs.biochem.5b00454 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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