- 著者
- Mika Sakamoto Hirofumi Suzuki Kei Yura
- 出版者
- The Biophysical Society of Japan
- 雑誌
- Biophysics and Physicobiology (ISSN:21894779)
- 巻号頁・発行日
- vol.16, pp.68-79, 2019 (Released:2019-02-15)
- 参考文献数
- 41
- 被引用文献数
- 3 4
Transport of small molecules across the cell membrane is a crucial biological mechanism for the maintenance of the cell activity. ABC transporter family is a huge group in the transporter membrane proteins and actively transports the substrates using the energy derived from ATP hydrolysis. In humans, there are 48 distinct genes for ABC transporters. A variation of a single amino acid in the amino acid sequence of ABC transporter has been known to be linked with certain disease. The mechanism of the onset of the disease by the variation is, however, still unclear. Recent progress in the method to measure the structures of huge membrane proteins has enabled determination of the 3D structures of ABC transporters and the accumulation of coordinate data of ABC transporter has enabled us to obtain clues for the onset of the disease caused by a single variation of amino acid residue. We compared the structures of ABC transporter in apo and ATP-binding forms and found a possible conformation shift around pivot-like residues in the transmembrane domains. When this conformation change in ABC transporter and the location of pathogenic variation were compared, we found a reasonable match between the two, explaining the onset of the disease by the variation. They likely cause impairment of the pivot-like movement, weakening of ATP binding and weakening of membrane surface interactions. These findings will give a new interpretation of the variations on ABC transporter genes and pave a way to analyse the effect of variation on protein structure and function.
- 著者
- Ha T. T. Duong Hirofumi Suzuki Saki Katagiri Mayu Shibata Misae Arai Kei Yura
- 出版者
- The Biophysical Society of Japan
- 雑誌
- Biophysics and Physicobiology (ISSN:21894779)
- 巻号頁・発行日
- vol.19, pp.e190025, 2022 (Released:2022-08-20)
- 参考文献数
- 46
Sequencing of individual human genomes enables studying relationship among nucleotide variations, amino acid substitutions, effect on protein structures and diseases. Many studies have found general tendencies, for instance, that pathogenic variations tend to be found in the buried regions of the protein structures, that benign variations tend to be found on the surface of the proteins, and that variations on evolutionary conserved residues tend to be pathogenic. These tendencies were deduced from globular proteins with standard evolutionary changes in amino acid sequences. In this study, we investigated the variation distribution on actin, one of the highly conserved proteins. Many nucleotide variations and three-dimensional structures of actin have been registered in databases. By combining those data, we found that variations buried inside the protein were rather benign and variations on the surface of the protein were pathogenic. This idiosyncratic distribution of the variation impact is likely ascribed to the extensive use of the surface of the protein for protein-protein interactions in actin.