Secondary Structure in the Core of Amyloid Fibrils Formed from Human 尾2m and its Truncated Variant 螖N6

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• 作者：Yongchao Su ; Claire J. Sarell ; Matthew T. Eddy ; Galia T. Debelouchina ; Loren B. Andreas ; Clare L. Pashley ; Sheena E. Radford ; Robert G. Griffin
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：April 30, 2014
• 年：2014
• 卷：136
• 期：17
• 页码：6313-6325
• 全文大小：928K
• 年卷期：v.136,no.17(April 30, 2014)
• ISSN：1520-5126

文摘

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 尾b>2b>-microglobulin (h尾b>2b>m) and a truncation variant, 螖N6 which lacks the N-terminal six amino acids. These fibrils are assembled from initially natively folded proteins with an all antiparallel 尾-stranded structure. Here, backbone conformations of wild-type h尾b>2b>m and 螖N6 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 尾-strands in their native immunoglobulin folds. The identification of seven 尾-strands in h尾b>2b>m fibrils indicates that approximately 70 residues are in a 尾-strand conformation in the fibril core. By contrast, nine 尾-strands comprise the fibrils formed from 螖N6, indicating a more extensive core. The precise location and length of 尾-strands in the two fibril forms also differ. The results indicate fibrils of 螖N6 and h尾b>2b>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.