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Edited by Ehud Gazit, Tel Aviv University, Tel Aviv, Israel, and accepted by Editorial Board Member Lia Addadi September 27, 2019 (received for review June 7, 2019)
Significance
The increase in life expectancy has nowadays positioned neurodegenerative diseases as a leading cause of death. Neurodegeneration is related to early amyloid protein aggregation; however, in the lack of an aggregation mechanism, neurodegenerative diseases still remain neither cured nor prevented. In a fundamental study of amyloid early aggregation, we have characterized the nanomechanical properties of steric zippers, the shortest amyloid sequences that yet bear high propensity to form fibers. We have found that steric zippers form unprecedented globular structures on route to fiber formation that exhibit a characteristic nanomechanical fingerprint. Approaching amyloid fiber formation from a basic physical perspective, this study sheds light on the internal structure of amyloid precursor chains, providing insight into the design of antiamyloid drugs.
Abstract
The term amyloid defines a group of proteins that aggregate into plaques or fibers. Amyloid fibers gained their fame mostly due to their relation with neurodegenerative diseases in humans. However, secreted by lower organisms, such as bacteria and fungi, amyloid fibers play a functional role: for example, when they serve as cement in the extracellular matrix of biofilms. Originating either in humans or in microorganisms, the sequence of amyloid proteins is decorated with hexapeptides with high propensity to form fibers, known as steric zippers. We have found that steric zippers form globular structures on route to making fibers and exhibit a characteristic force–distance (F-D) fingerprint when pulled with an atomic force microscope (AFM) tip. Particularly, the F-D pulling curves showed force plateau steps, suggesting that the globular structures were composed of chains that were unwound like a yarn ball. Force plateau analysis showed that the F-D characteristic parameters were sequence sensitive, representing differences in the packing of the hexapeptides within the globules. These unprecedented findings show that steric zippers exhibit a characteristic nanomechanical signature in solution in addition to previously observed characteristic crystallographic structure. Getting to the fundamental interactions that govern the unzipping of full-length amyloid fibers may initiate the development of antiamyloid methods that target the physical in addition to the structural properties of steric zippers.
Footnotes
- ↵1To whom correspondence may be addressed. Email: liraz.chai{at}mail.huji.ac.il.
Author contributions: N.L.-Z. and L.C. designed research; N.L.-Z. and M.G. performed research; N.L.-Z., M.G., and L.C. analyzed data; and N.L.-Z., M.G., and L.C. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission. E.G. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1908782116/-/DCSupplemental.
Published under the PNAS license.
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Nanomechanical properties of steric zipper globular structures
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- Physical Sciences
- Biophysics and Computational Biology
- Biological Sciences
- Biochemistry
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