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Protein Sci. 2008 Sep;17(9):1617-23. doi: 10.1110/ps.036368.108. Epub 2008 Jun 13.

The structure of a fibril-forming sequence, NNQQNY, in the context of a globular fold.

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Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, Molecular Biology Institute, UCLA, Los Angeles, California 90095-1570, USA.


Numerous human disorders are associated with the formation of protein fibrils. The fibril-forming capacity of a protein has been found in recent studies to be determined by a short segment of residues that forms a dual beta-sheet, called a steric zipper, in the spine of the fibril. The question arises as to whether a fibril-forming segment, when inserted within the sequence of a globular protein, will invariably cause the protein to form fibrils. Here we investigate this question by inserting the known fibril-forming segment NNQQNY into the globular enzyme, T7 endonuclease I. From earlier studies, we know that in its fibril form, NNQQNY is in an extended conformation. We first found that the inserted NNQQNY stimulates fibril formation of T7 endonuclease I in solution. Thus NNQQNY within T7 endonuclease I can exist in an extended conformation, capable of forming the steric zipper in the core of a fibril. We also found that T7 endonuclease I folds into a decamer that does not form fibrils. We determined the structure of the decamer by X-ray crystallography, finding an unusual oligomer without point group symmetry, and finding that the NNQQNY segments within the decamer adopt two twisted conformations, neither is apparently able to fibrillize. We conclude that twisting of fibril forming sequences from the fully extended conformation, imposed by the context of their placement in proteins, can interfere with fibril formation.

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