Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6
Amyloid fibrils formed from initially soluble proteins with diverse sequences are associated with an array of human diseases. In the human disorder, dialysis-related amyloidosis (DRA), fibrils contain two major constituents, full-length human β[subscript 2]-microglobulin (hβ2m) and a truncation vari...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2015
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| Online Access: | http://hdl.handle.net/1721.1/94626 https://orcid.org/0000-0002-3349-6212 https://orcid.org/0000-0003-1589-832X |
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| author | Su, Yongchao Sarell, Claire J. Eddy, Matthew Thomas Debelouchina, Galia Tzvetanova Andreas, Loren Pashley, Clare L. Radford, Sheena E. Griffin, Robert Guy |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Su, Yongchao Sarell, Claire J. Eddy, Matthew Thomas Debelouchina, Galia Tzvetanova Andreas, Loren Pashley, Clare L. Radford, Sheena E. Griffin, Robert Guy |
| author_sort | Su, Yongchao |
| collection | MIT |
| description | Amyloid fibrils formed from initially soluble proteins with diverse sequences are associated with an array of human diseases. In the human disorder, dialysis-related amyloidosis (DRA), fibrils contain two major constituents, full-length human β[subscript 2]-microglobulin (hβ2m) and a truncation variant, ΔN6 which lacks the N-terminal six amino acids. These fibrils are assembled from initially natively folded proteins with an all antiparallel β-stranded structure. Here, backbone conformations of wild-type hβ[subscript 2]m and ΔN6 in their amyloid forms have been determined using a combination of dilute isotopic labeling strategies and multidimensional magic angle spinning (MAS) NMR techniques at high magnetic fields, providing valuable structural information at the atomic-level about the fibril architecture. The secondary structures of both fibril types, determined by the assignment of ~80% of the backbone resonances of these 100- and 94-residue proteins, respectively, reveal substantial backbone rearrangement compared with the location of β-strands in their native immunoglobulin folds. The identification of seven β-strands in hβ[subscript 2]m fibrils indicates that approximately 70 residues are in a β-strand conformation in the fibril core. By contrast, nine β-strands comprise the fibrils formed from ΔN6, indicating a more extensive core. The precise location and length of β-strands in the two fibril forms also differ. The results indicate fibrils of ΔN6 and hβ[subscript 2]m have an extensive core architecture involving the majority of residues in the polypeptide sequence. The common elements of the backbone structure of the two proteins likely facilitates their ability to copolymerize during amyloid fibril assembly. |
| first_indexed | 2024-09-23T11:37:56Z |
| format | Article |
| id | mit-1721.1/94626 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:37:56Z |
| publishDate | 2015 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/946262022-10-01T04:55:29Z Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6 Su, Yongchao Sarell, Claire J. Eddy, Matthew Thomas Debelouchina, Galia Tzvetanova Andreas, Loren Pashley, Clare L. Radford, Sheena E. Griffin, Robert Guy Massachusetts Institute of Technology. Department of Chemistry Francis Bitter Magnet Laboratory (Massachusetts Institute of Technology) Su, Yongchao Eddy, Matthew Thomas Andreas, Loren Griffin, Robert Guy Amyloid fibrils formed from initially soluble proteins with diverse sequences are associated with an array of human diseases. In the human disorder, dialysis-related amyloidosis (DRA), fibrils contain two major constituents, full-length human β[subscript 2]-microglobulin (hβ2m) and a truncation variant, ΔN6 which lacks the N-terminal six amino acids. These fibrils are assembled from initially natively folded proteins with an all antiparallel β-stranded structure. Here, backbone conformations of wild-type hβ[subscript 2]m and ΔN6 in their amyloid forms have been determined using a combination of dilute isotopic labeling strategies and multidimensional magic angle spinning (MAS) NMR techniques at high magnetic fields, providing valuable structural information at the atomic-level about the fibril architecture. The secondary structures of both fibril types, determined by the assignment of ~80% of the backbone resonances of these 100- and 94-residue proteins, respectively, reveal substantial backbone rearrangement compared with the location of β-strands in their native immunoglobulin folds. The identification of seven β-strands in hβ[subscript 2]m fibrils indicates that approximately 70 residues are in a β-strand conformation in the fibril core. By contrast, nine β-strands comprise the fibrils formed from ΔN6, indicating a more extensive core. The precise location and length of β-strands in the two fibril forms also differ. The results indicate fibrils of ΔN6 and hβ[subscript 2]m have an extensive core architecture involving the majority of residues in the polypeptide sequence. The common elements of the backbone structure of the two proteins likely facilitates their ability to copolymerize during amyloid fibril assembly. National Institutes of Health (U.S.) (Grant EB-003151) National Institutes of Health (U.S.) (Grant EB-002026) 2015-02-18T21:47:07Z 2015-02-18T21:47:07Z 2014-03 2013-12 Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 http://hdl.handle.net/1721.1/94626 Su, Yongchao, Claire J. Sarell, Matthew T. Eddy, Galia T. Debelouchina, Loren B. Andreas, Clare L. Pashley, Sheena E. Radford, and Robert G. Griffin. “ Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6 .” Journal of the American Chemical Society 136, no. 17 (April 30, 2014): 6313–6325. https://orcid.org/0000-0002-3349-6212 https://orcid.org/0000-0003-1589-832X en_US http://dx.doi.org/10.1021/ja4126092 Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Su, Yongchao Sarell, Claire J. Eddy, Matthew Thomas Debelouchina, Galia Tzvetanova Andreas, Loren Pashley, Clare L. Radford, Sheena E. Griffin, Robert Guy Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6 |
| title | Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6 |
| title_full | Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6 |
| title_fullStr | Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6 |
| title_full_unstemmed | Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6 |
| title_short | Secondary Structure in the Core of Amyloid Fibrils Formed from Human β [subscript 2] m and Its Truncated Variant ΔN6 |
| title_sort | secondary structure in the core of amyloid fibrils formed from human β subscript 2 m and its truncated variant δn6 |
| url | http://hdl.handle.net/1721.1/94626 https://orcid.org/0000-0002-3349-6212 https://orcid.org/0000-0003-1589-832X |
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