Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes
IBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase regulation, we assembled a full-l...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/15/8079 |
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| author | Purbasha Nandi Shan Li Rod Carlo A. Columbres Feng Wang Dewight R. Williams Yu-Ping Poh Tsui-Fen Chou Po-Lin Chiu |
| author_facet | Purbasha Nandi Shan Li Rod Carlo A. Columbres Feng Wang Dewight R. Williams Yu-Ping Poh Tsui-Fen Chou Po-Lin Chiu |
| author_sort | Purbasha Nandi |
| collection | DOAJ |
| description | IBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase regulation, we assembled a full-length p97<sup>R155H</sup> with its p47 cofactor and first visualized their structures using single-particle cryo-EM. More than one-third of the population was the dodecameric form. Nucleotide presence dissociates the dodecamer into two hexamers for its highly elevated function. The N-domains of the p97<sup>R155H</sup> mutant all show up configurations in ADP- or ATP<i>γ</i>S-bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97<sup>R155H</sup> ATPase activities via changing the conformations of arginine fingers. These functional and structural analyses underline the ATPase dysregulation with the miscommunication between the functional modules of the p97<sup>R155H</sup>. |
| first_indexed | 2024-03-10T09:15:10Z |
| format | Article |
| id | doaj.art-9f08726992584fa1ba2a51f08262e895 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:15:10Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9f08726992584fa1ba2a51f08262e8952023-11-22T05:42:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012215807910.3390/ijms22158079Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant ComplexesPurbasha Nandi0Shan Li1Rod Carlo A. Columbres2Feng Wang3Dewight R. Williams4Yu-Ping Poh5Tsui-Fen Chou6Po-Lin Chiu7Biodesign Center for Applied Structural Discovery, School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USADivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USADivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USADivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USAEyring Materials Center, Arizona State University, Tempe, AZ 85287, USADivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USADivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USABiodesign Center for Applied Structural Discovery, School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USAIBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase regulation, we assembled a full-length p97<sup>R155H</sup> with its p47 cofactor and first visualized their structures using single-particle cryo-EM. More than one-third of the population was the dodecameric form. Nucleotide presence dissociates the dodecamer into two hexamers for its highly elevated function. The N-domains of the p97<sup>R155H</sup> mutant all show up configurations in ADP- or ATP<i>γ</i>S-bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97<sup>R155H</sup> ATPase activities via changing the conformations of arginine fingers. These functional and structural analyses underline the ATPase dysregulation with the miscommunication between the functional modules of the p97<sup>R155H</sup>.https://www.mdpi.com/1422-0067/22/15/8079p97 ATPasep97<sup>R155H</sup> mutationp47 cofactorarginine fingerIBMPFDsingle-particle cryo-EM |
| spellingShingle | Purbasha Nandi Shan Li Rod Carlo A. Columbres Feng Wang Dewight R. Williams Yu-Ping Poh Tsui-Fen Chou Po-Lin Chiu Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes International Journal of Molecular Sciences p97 ATPase p97<sup>R155H</sup> mutation p47 cofactor arginine finger IBMPFD single-particle cryo-EM |
| title | Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes |
| title_full | Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes |
| title_fullStr | Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes |
| title_full_unstemmed | Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes |
| title_short | Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes |
| title_sort | structural and functional analysis of disease linked p97 atpase mutant complexes |
| topic | p97 ATPase p97<sup>R155H</sup> mutation p47 cofactor arginine finger IBMPFD single-particle cryo-EM |
| url | https://www.mdpi.com/1422-0067/22/15/8079 |
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