ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1
Abstract ALS-causing C71G-hPFN1 coexists in both folded and unfolded states, while nascent hSOD1 is unfolded. So far, the mechanisms underlying their ALS-triggering potential remain enigmatic. Here we show by NMR that ATP completely converts C71G-hPFN1 into the folded state at a 1:2 ratio, while ind...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-023-00997-0 |
| _version_ | 1797577558614605824 |
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| author | Jian Kang Liangzhong Lim Jianxing Song |
| author_facet | Jian Kang Liangzhong Lim Jianxing Song |
| author_sort | Jian Kang |
| collection | DOAJ |
| description | Abstract ALS-causing C71G-hPFN1 coexists in both folded and unfolded states, while nascent hSOD1 is unfolded. So far, the mechanisms underlying their ALS-triggering potential remain enigmatic. Here we show by NMR that ATP completely converts C71G-hPFN1 into the folded state at a 1:2 ratio, while inducing nascent hSOD1 into two co-existing states at a 1:8 ratio. Surprisingly, the inducing capacity of ATP comes from its triphosphate, but free triphosphate triggers aggregation. The inducing capacity ranks as: ATP = ATPP = PPP > ADP = AMP−PNP = AMP−PCP = PP, while AMP, adenosine, P, and NaCl show no conversion. Mechanistically, ATP and triphosphate appear to enhance the intrinsic folding capacity encoded in the sequences, as unveiled by comparing conformations and dynamics of ATP- and Zn2+-induced hSOD1 folded states. Our study provides a mechanism for the finding that some single-cell organisms employ polyphosphates as primordial chaperones, and sheds light on the enigma of age-related onset of familial ALS and risk increase of neurodegenerative diseases. |
| first_indexed | 2024-03-10T22:10:02Z |
| format | Article |
| id | doaj.art-2796aaac2c2643f993587b46d541cdd3 |
| institution | Directory Open Access Journal |
| issn | 2399-3669 |
| language | English |
| last_indexed | 2024-03-10T22:10:02Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj.art-2796aaac2c2643f993587b46d541cdd32023-11-19T12:37:48ZengNature PortfolioCommunications Chemistry2399-36692023-09-016111510.1038/s42004-023-00997-0ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1Jian Kang0Liangzhong Lim1Jianxing Song2Department of Biological Sciences, Faculty of Science, National University of SingaporeDepartment of Biological Sciences, Faculty of Science, National University of SingaporeDepartment of Biological Sciences, Faculty of Science, National University of SingaporeAbstract ALS-causing C71G-hPFN1 coexists in both folded and unfolded states, while nascent hSOD1 is unfolded. So far, the mechanisms underlying their ALS-triggering potential remain enigmatic. Here we show by NMR that ATP completely converts C71G-hPFN1 into the folded state at a 1:2 ratio, while inducing nascent hSOD1 into two co-existing states at a 1:8 ratio. Surprisingly, the inducing capacity of ATP comes from its triphosphate, but free triphosphate triggers aggregation. The inducing capacity ranks as: ATP = ATPP = PPP > ADP = AMP−PNP = AMP−PCP = PP, while AMP, adenosine, P, and NaCl show no conversion. Mechanistically, ATP and triphosphate appear to enhance the intrinsic folding capacity encoded in the sequences, as unveiled by comparing conformations and dynamics of ATP- and Zn2+-induced hSOD1 folded states. Our study provides a mechanism for the finding that some single-cell organisms employ polyphosphates as primordial chaperones, and sheds light on the enigma of age-related onset of familial ALS and risk increase of neurodegenerative diseases.https://doi.org/10.1038/s42004-023-00997-0 |
| spellingShingle | Jian Kang Liangzhong Lim Jianxing Song ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1 Communications Chemistry |
| title | ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1 |
| title_full | ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1 |
| title_fullStr | ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1 |
| title_full_unstemmed | ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1 |
| title_short | ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1 |
| title_sort | atp induces folding of als causing c71g hpfn1 and nascent hsod1 |
| url | https://doi.org/10.1038/s42004-023-00997-0 |
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