4E0L

FYLLYYT segment from human Beta 2 Microglobulin (62-68) displayed on 54-membered macrocycle scaffold

Summary for 4E0L

• Entry DOI: 10.2210/pdb4e0l/pdb
• Related: 4E0K 4E0M 4E0N 4E0O
• Descriptor: Cyclic pseudo-peptide FYLLYYT(ORN)KN(HAO)SA(ORN), (4S)-2-METHYL-2,4-PENTANEDIOL (3 entities in total)
• Functional Keywords: amyloid, out-of-register, fiber-forming, macrocycle, protein fibril
• Total number of polymer chains: 4
• Total formula weight: 7624.57

Authors

Zhao, M.,Liu, C.,Michael, S.R.,Eisenberg, D. (deposition date: 2012-03-04, release date: 2012-12-19, Last modification date: 2023-11-15)

Primary citation

Liu, C.,Zhao, M.,Jiang, L.,Cheng, P.N.,Park, J.,Sawaya, M.R.,Pensalfini, A.,Gou, D.,Berk, A.J.,Glabe, C.G.,Nowick, J.,Eisenberg, D.
Out-of-register beta-sheets suggest a pathway to toxic amyloid aggregates.
Proc.Natl.Acad.Sci.USA, 109:20913-20918, 2012

PubMed Abstract: Although aberrant protein aggregation has been conclusively linked to dozens of devastating amyloid diseases, scientists remain puzzled about the molecular features that render amyloid fibrils or small oligomers toxic. Here, we report a previously unobserved type of amyloid fibril that tests as cytotoxic: one in which the strands of the contributing β-sheets are out of register. In all amyloid fibrils previously characterized at the molecular level, only in-register β-sheets have been observed, in which each strand makes its full complement of hydrogen bonds with the strands above and below it in the fibril. In out-of-register sheets, strands are sheared relative to one another, leaving dangling hydrogen bonds. Based on this finding, we designed out-of-register β-sheet amyloid mimics, which form both cylindrin-like oligomers and fibrils, and these mimics are cytotoxic. Structural and energetic considerations suggest that out-of-register fibrils can readily convert to toxic cylindrins. We propose that out-of-register β-sheets and their related cylindrins are part of a toxic amyloid pathway, which is distinct from the more energetically favored in-register amyloid pathway.

PubMed: 23213214
DOI: 10.1073/pnas.1218792109

Experimental method

X-RAY DIFFRACTION (1.7 Å)