A conserved residue in the P2X4 receptor has a nonconserved function in ATP recognition
| Autor: | Yun Tian, Changzhu Li, Liang-Fei Sun, Ye Yu, Zhihong Xiao, Michael X. Zhu, Jin Wang, Pei-Wang Li, Xue-Fei Ma, Ping-Fang Chen, Ying-Zhe Fan, Chang-Run Guo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular structure–function Molecular model Protein Conformation channel gating HEK293 human embryonic kidney 293 hP2X3 human (Homo sapiens) P2X3 Protein Data Bank (RCSB PDB) Sequence Homology AmP2X gulf coast tick (Amblyomma maculatum) P2X purinergic receptor Biochemistry 03 medical and health sciences Residue (chemistry) Adenosine Triphosphate PDB Protein Data Bank Animals Humans Amino Acid Sequence Molecular Biology Ion channel Zebrafish chemistry.chemical_classification 030102 biochemistry & molecular biology pdP2X7 giant panda (Ailuropoda melanoleuca) P2X7 Purinergic receptor HEK 293 cells ckP2X7 chicken (Gallus gallus domesticus) P2X7 rP2X7 rat (Rattus norvegicus) P2X7 Cell Biology computer.file_format Protein Data Bank electrophysiology MD molecular dynamics molecular dynamics Cell biology Amino acid 030104 developmental biology HEK293 Cells chemistry ion channel side-chain orientation RSSF relationship between sequence structure and function zfP2X4 zebrafish (Danio rerio) P2X4 computer Ion Channel Gating Receptors Purinergic P2X4 Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Highly conserved amino acids are generally anticipated to have similar functions across a protein superfamily, including that of the P2X ion channels, which are gated by extracellular ATP. However, whether and how these functions are conserved becomes less clear when neighboring amino acids are not conserved. Here, we investigate one such case, focused on the highly conserved residue from P2X4, E118 (rat P2X4 numbering, rP2X4), a P2X subtype associated with human neuropathic pain. When we compared the crystal structures of P2X4 with those of other P2X subtypes, including P2X3, P2X7, and AmP2X, we observed a slightly altered side-chain orientation of E118. We used protein chimeras, double-mutant cycle analysis, and molecular modeling to reveal that E118 forms specific contacts with amino acids in the "beak" region, which facilitates ATP binding to rP2X4. These contacts are not present in other subtypes because of sequence variance in the beak region, resulting in decoupling of this conserved residue from ATP recognition and/or channel gating of P2X receptors. Our study provides an example of a conserved residue with a specific role in functional proteins enabled by adjacent nonconserved residues. The unique role established by the E118-beak region contact provides a blueprint for the development of subtype-specific inhibitors of P2X4. |
| Databáze: | OpenAIRE |
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