Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70
Abstract Maintenance of protein homeostasis is necessary for cell viability and depends on a complex network of chaperones and co-chaperones, including the heat-shock protein 70 (Hsp70) system. In human mitochondria, mitochondrial Hsp70 (mortalin) and the nucleotide exchange factor (GrpEL1) work syn...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54499-1 |
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| author | Marc A. Morizono Kelly L. McGuire Natalie I. Birouty Mark A. Herzik |
| author_facet | Marc A. Morizono Kelly L. McGuire Natalie I. Birouty Mark A. Herzik |
| author_sort | Marc A. Morizono |
| collection | DOAJ |
| description | Abstract Maintenance of protein homeostasis is necessary for cell viability and depends on a complex network of chaperones and co-chaperones, including the heat-shock protein 70 (Hsp70) system. In human mitochondria, mitochondrial Hsp70 (mortalin) and the nucleotide exchange factor (GrpEL1) work synergistically to stabilize proteins, assemble protein complexes, and facilitate protein import. However, our understanding of the molecular mechanisms guiding these processes is hampered by limited structural information. To elucidate these mechanistic details, we used cryoEM to determine structures of full-length human mortalin-GrpEL1 complexes in previously unobserved states. Our structures and molecular dynamics simulations allow us to delineate specific roles for mortalin-GrpEL1 interfaces and to identify steps in GrpEL1-mediated nucleotide and substrate release by mortalin. Subsequent analyses reveal conserved mechanisms across bacteria and mammals and facilitate a complete understanding of sequential nucleotide and substrate release for the Hsp70 chaperone system. |
| format | Article |
| id | doaj-art-8182965103c44d51a21c003086770170 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8182965103c44d51a21c0030867701702025-01-05T12:36:19ZengNature PortfolioNature Communications2041-17232024-12-0115111710.1038/s41467-024-54499-1Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70Marc A. Morizono0Kelly L. McGuire1Natalie I. Birouty2Mark A. Herzik3Department of Chemistry and Biochemistry, University of California, San DiegoDepartment of Chemistry and Biochemistry, University of California, San DiegoDepartment of Chemistry and Biochemistry, University of California, San DiegoDepartment of Chemistry and Biochemistry, University of California, San DiegoAbstract Maintenance of protein homeostasis is necessary for cell viability and depends on a complex network of chaperones and co-chaperones, including the heat-shock protein 70 (Hsp70) system. In human mitochondria, mitochondrial Hsp70 (mortalin) and the nucleotide exchange factor (GrpEL1) work synergistically to stabilize proteins, assemble protein complexes, and facilitate protein import. However, our understanding of the molecular mechanisms guiding these processes is hampered by limited structural information. To elucidate these mechanistic details, we used cryoEM to determine structures of full-length human mortalin-GrpEL1 complexes in previously unobserved states. Our structures and molecular dynamics simulations allow us to delineate specific roles for mortalin-GrpEL1 interfaces and to identify steps in GrpEL1-mediated nucleotide and substrate release by mortalin. Subsequent analyses reveal conserved mechanisms across bacteria and mammals and facilitate a complete understanding of sequential nucleotide and substrate release for the Hsp70 chaperone system.https://doi.org/10.1038/s41467-024-54499-1 |
| spellingShingle | Marc A. Morizono Kelly L. McGuire Natalie I. Birouty Mark A. Herzik Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70 Nature Communications |
| title | Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70 |
| title_full | Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70 |
| title_fullStr | Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70 |
| title_full_unstemmed | Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70 |
| title_short | Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70 |
| title_sort | structural insights into grpel1 mediated nucleotide and substrate release of human mitochondrial hsp70 |
| url | https://doi.org/10.1038/s41467-024-54499-1 |
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