RNA-binding protein TLS/FUS is a causative gene for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TLS mutations induce the propensity of TLS to form aggregates in motor neurons causing neuronal degenerative lesions to their necrosis. TLS is prone to be precipitated in high concentration around 10 mg/ml, while mutated TLS is suspected to be precipitated even lower or physiological concentration in the motor neurons. An unidentified agent from infections would cause formation of the precipitation of TLS through their surface antigens. The precipitation driven with agents might be attribute to a small compound appeared on the surface. Biotinylated isoxazole (BISOX) has been reported to be precipitated with divergent RNA-binding proteins including TLS in nuclear extracts of cultured mammalian cells. We have published a molecular model for crystal formation of BISOX with TLS providing a plat form for searching novel regulators to precipitate TLS in neuronal disorders. Because BISOX is an artificial compound, we have further explored to obtain naturally occurring agents to induce the TLS precipitation and generated a conceivable biological compound, biotin-Lys-His (BLH). We have examined the precipitation of BLH with HeLa cell nuclear extract, but did not detect any TLS signal. Then, we add BLH to reaction of BISOX with TLS, and serendipitously observed a robust inhibitory effect of BLH on the formation of crystal of BISOX with TLS. We employed in silico analysis to show how BLH blocks the crystal formation of BISOX with TLS. The computational analysis of the events presented a model that BLH should be incorporated into the crystal formation of BISOX but some steric hindrance placed by BLH blocks growing of the crystal of BISOX and TLS. These results provide the potentiality that BLH should block the aggregate formation of TLS in ALS, leading to a seed for drug discovery against ALS, although it needs future endeavor to find more compounds to have effect on the TLS aggregation.
| Published in | Biomedical Sciences (Volume 3, Issue 4) |
| DOI | 10.11648/j.bs.20170304.11 |
| Page(s) | 67-77 |
| Creative Commons |
This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited. |
| Copyright |
Copyright © The Author(s), 2017. Published by Science Publishing Group |
TLS, FUS, Biotinylated Isoxazole, Biotin-Lys-His, Low Complexity Domain, Amyotrophic Lateral Sclerosis
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APA Style
Naomi Ueda, Gengo Kashiwazaki, Toshikazu Bando, Riki Kurokawa. (2017). Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis. Biomedical Sciences, 3(4), 67-77. https://doi.org/10.11648/j.bs.20170304.11
ACS Style
Naomi Ueda; Gengo Kashiwazaki; Toshikazu Bando; Riki Kurokawa. Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis. Biomed. Sci. 2017, 3(4), 67-77. doi: 10.11648/j.bs.20170304.11
AMA Style
Naomi Ueda, Gengo Kashiwazaki, Toshikazu Bando, Riki Kurokawa. Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis. Biomed Sci. 2017;3(4):67-77. doi: 10.11648/j.bs.20170304.11
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Download@article{10.11648/j.bs.20170304.11,
author = {Naomi Ueda and Gengo Kashiwazaki and Toshikazu Bando and Riki Kurokawa},
title = {Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis},
journal = {Biomedical Sciences},
volume = {3},
number = {4},
pages = {67-77},
doi = {10.11648/j.bs.20170304.11},
url = {https://doi.org/10.11648/j.bs.20170304.11},
eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bs.20170304.11},
abstract = {RNA-binding protein TLS/FUS is a causative gene for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TLS mutations induce the propensity of TLS to form aggregates in motor neurons causing neuronal degenerative lesions to their necrosis. TLS is prone to be precipitated in high concentration around 10 mg/ml, while mutated TLS is suspected to be precipitated even lower or physiological concentration in the motor neurons. An unidentified agent from infections would cause formation of the precipitation of TLS through their surface antigens. The precipitation driven with agents might be attribute to a small compound appeared on the surface. Biotinylated isoxazole (BISOX) has been reported to be precipitated with divergent RNA-binding proteins including TLS in nuclear extracts of cultured mammalian cells. We have published a molecular model for crystal formation of BISOX with TLS providing a plat form for searching novel regulators to precipitate TLS in neuronal disorders. Because BISOX is an artificial compound, we have further explored to obtain naturally occurring agents to induce the TLS precipitation and generated a conceivable biological compound, biotin-Lys-His (BLH). We have examined the precipitation of BLH with HeLa cell nuclear extract, but did not detect any TLS signal. Then, we add BLH to reaction of BISOX with TLS, and serendipitously observed a robust inhibitory effect of BLH on the formation of crystal of BISOX with TLS. We employed in silico analysis to show how BLH blocks the crystal formation of BISOX with TLS. The computational analysis of the events presented a model that BLH should be incorporated into the crystal formation of BISOX but some steric hindrance placed by BLH blocks growing of the crystal of BISOX and TLS. These results provide the potentiality that BLH should block the aggregate formation of TLS in ALS, leading to a seed for drug discovery against ALS, although it needs future endeavor to find more compounds to have effect on the TLS aggregation.},
year = {2017}
}
TY - JOUR T1 - Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis AU - Naomi Ueda AU - Gengo Kashiwazaki AU - Toshikazu Bando AU - Riki Kurokawa Y1 - 2017/09/12 PY - 2017 N1 - https://doi.org/10.11648/j.bs.20170304.11 DO - 10.11648/j.bs.20170304.11 T2 - Biomedical Sciences JF - Biomedical Sciences JO - Biomedical Sciences SP - 67 EP - 77 PB - Science Publishing Group SN - 2575-3932 UR - https://doi.org/10.11648/j.bs.20170304.11 AB - RNA-binding protein TLS/FUS is a causative gene for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TLS mutations induce the propensity of TLS to form aggregates in motor neurons causing neuronal degenerative lesions to their necrosis. TLS is prone to be precipitated in high concentration around 10 mg/ml, while mutated TLS is suspected to be precipitated even lower or physiological concentration in the motor neurons. An unidentified agent from infections would cause formation of the precipitation of TLS through their surface antigens. The precipitation driven with agents might be attribute to a small compound appeared on the surface. Biotinylated isoxazole (BISOX) has been reported to be precipitated with divergent RNA-binding proteins including TLS in nuclear extracts of cultured mammalian cells. We have published a molecular model for crystal formation of BISOX with TLS providing a plat form for searching novel regulators to precipitate TLS in neuronal disorders. Because BISOX is an artificial compound, we have further explored to obtain naturally occurring agents to induce the TLS precipitation and generated a conceivable biological compound, biotin-Lys-His (BLH). We have examined the precipitation of BLH with HeLa cell nuclear extract, but did not detect any TLS signal. Then, we add BLH to reaction of BISOX with TLS, and serendipitously observed a robust inhibitory effect of BLH on the formation of crystal of BISOX with TLS. We employed in silico analysis to show how BLH blocks the crystal formation of BISOX with TLS. The computational analysis of the events presented a model that BLH should be incorporated into the crystal formation of BISOX but some steric hindrance placed by BLH blocks growing of the crystal of BISOX and TLS. These results provide the potentiality that BLH should block the aggregate formation of TLS in ALS, leading to a seed for drug discovery against ALS, although it needs future endeavor to find more compounds to have effect on the TLS aggregation. VL - 3 IS - 4 ER -
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