In a stunning discovery, scientists have found the first natural example of an amyloid made entirely of α-helices, instead of the typical β-sheets. The fibril comes from none other than the bacterium Staphylococcus aureus, notorious for its stubborn resistance to antibiotics and its penchant for causing deadly infections. Scientists led by Meytal Landau, Technion-Israel Institute of Technology, Haifa, report in the February 24 Science that this helical fibrillation makes the secreted protein, PSMa3, extremely toxic to human cells. 

Deadly Threads.

Artistic rendering of how S. aureus bacteria (yellow) secrete PSMα3, which forms fibrils (strands) toxic to human T cells (blue). [Dima Abelski, Dimedia.]

“This is mind-blowing for a structural biologist,” said Landau. “To zoom in on something that looks exactly like an amyloid, and find α-helices instead of β-strands—it’s a total paradigm shift.”

PSMα3, short for phenol-soluble modulin α3, is a member of a family of virulent peptides secreted by bacteria to attack their hosts. The peptides cause inflammation, lyse cells, and help form biofilms. Methicillin-resistant S. aureus (MRSA) secretes unusually large amounts of PSMα3. The peptide has 22 residues that curl into an amphipathic α-helix—hydrophilic on one side and hydrophobic on the other. Other family members have been reported to form β-rich fibrils, but not PSMα3 (Schwartz et al., 2012).

First authors Einav Tayeb-Fligelman, Orly Tabachnikov, and Asher Moshe found under an electron microscope that PSMα3 does indeed stack into fibrils, ones that bind the amyloid-detecting dye Thioflavin T (see image below). To the authors’ surprise, biophysical techniques revealed that PSMα3 retained its α-helical structure within the fibrils—the hydrophobic regions pressing together and the hydrophilic ones facing the outside. Not only that, this fibrillization appeared to be necessary for PSMα3’s cytotoxicity. A mutant that kept the α-helical shape but did not form fibrils was less toxic to human immune cells than normal PSMα3 or another mutant that formed fibrils. Disrupting PSMα3 fibrillization with a surfactant also protected cells. The authors guess that the fibrils form “carpets” on the cell membrane that deform it.

Curly Surprise: The PSMα3 peptide (C) forms fibrils (A) that bind Thioflavin T (B). A fibril viewed from the top (D) reveals hydrophobic regions of the helix inside the fiber and hydrophyllic regions outside. A side view of the fiber (E) depicts eight helices lying atop one another. [Science/AAAS.]

This is likely just the first example of an α-amyloid in nature, said Landau. She expects more to turn up in bacteria and eukaryotes. Some peptides that form disease-associated amyloids in eukaryotes, including α-synuclein, Aβ, and the yeast prion Ure2p, exhibit α-helical structures in their monomer or pre-fibrillar states, the authors noted (Ghosh et al., 2015; Bousset et al., 2002Kirkitadze et al., 2001). However, there is no evidence yet to suggest this α-amyloid fibril is related to those structures, said Landau.

Besides looking for other examples of cross-α fibrils in nature, she plans to design inhibitors for them and determine how they kill cells. There is evidence that some bacterial amyloids may seed formation of human amyloids, such as α-synuclein (see Oct 2016 news).—Gwyneth Dickey Zakaib



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News Citations

  1. Could Bacterial Amyloid Trigger Parkinson’s Pathology?

Paper Citations

  1. . Functional amyloids composed of phenol soluble modulins stabilize Staphylococcus aureus biofilms. PLoS Pathog. 2012;8(6):e1002744. Epub 2012 Jun 7 PubMed.
  2. . Structure based aggregation studies reveal the presence of helix-rich intermediate during α-Synuclein aggregation. Sci Rep. 2015 Mar 18;5:9228. PubMed.
  3. . The yeast prion Ure2p retains its native alpha-helical conformation upon assembly into protein fibrils in vitro. EMBO J. 2002 Jun 17;21(12):2903-11. PubMed.
  4. . Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. J Mol Biol. 2001 Oct 5;312(5):1103-19. PubMed.

Further Reading