Effect of rare coding variants of charged amino acid residues on the function of human organic anion transporting polypeptide 1B3 (SLCO1B3)
| Autor: | Hongjian Zhang, Zhongmin Wang, Shuai Liu, Chunshan Gui, Ying Li, Taotao Peng |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Nonsynonymous substitution Biophysics Phospholipid medicine.disease_cause Biochemistry Solute Carrier Organic Anion Transporter Family Member 1B3 Structure-Activity Relationship 03 medical and health sciences Residue (chemistry) chemistry.chemical_compound 0302 clinical medicine Protein Domains medicine Humans Nucleotide Molecular Biology Cells Cultured chemistry.chemical_classification Mutation biology Biological Transport Cell Biology Organic anion-transporting polypeptide Transmembrane domain 030104 developmental biology Amino Acid Substitution Liver chemistry 030220 oncology & carcinogenesis Mutagenesis Site-Directed biology.protein Function (biology) |
| Zdroj: | Biochemical and Biophysical Research Communications. 557:1-7 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2021.03.169 |
| Popis: | Human organic anion transporting polypeptide 1B3 (OATP1B3, gene symbol SLCO1B3) is a liver-specific uptake transporter. Its function was reported to be largely affected by some positively charged amino acid residues. However, so far the effect of naturally occurring genetic variants of charged residues on OATP1B3’s function has not been explored yet. Therefore, in the present study nonsynonymous single nucleotide variants that led to the replacement of charged residues of OATP1B3 were investigated. Our results demonstrated that rare coding variants c.542G > A (p.R181H) and c.592G > A (p.D198N) had a great effect on the function of OATP1B3 mainly due to their influence on protein’s surface expression. Further mutation studies showed that a negatively charged residue at position 198 was indispensable to the proper expression of OATP1B3 on the plasma membrane, while a positively charged reside at position 181 was not a must. Structural modeling indicated that R181 is located at the center of putative transmembrane domain 4 (TM4) and its side chain faces towards TM2 instead of towards the substrate translocation pathway, whereas D198 is located at the border of TM4 and intracellular loop 2 and may electrostatically repulse negatively charged phospholipid head groups. In conclusion, our results indicated that rare coding variants that cause changes of charged amino acid residues might have large influence on the function and expression of OATP1B3. |
| Databáze: | OpenAIRE |
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