scholarly journals Extreme Amyloid Polymorphism in Staphylococcus aureus Virulent PSMα Peptides

2018 ◽  
Author(s):  
Nir Salinas ◽  
Jacques-Philippe Colletier ◽  
Asher Moshe ◽  
Meytal Landau
Keyword(s):  
Staphylococcus Aureus ◽  
High Stability ◽  
Amyloid Fibrils ◽  
Full Length ◽  
Naturally Occurring ◽  
Peptide Family ◽  
Β Amyloid ◽  
Β Sheets ◽  
The Cross ◽  
Functional Amyloids

AbstractMembers of the Staphylococcus aureus phenol-soluble modulin (PSM) peptide family are secreted as functional amyloids that serve diverse roles in pathogenicity and may be present as full-length peptides or as naturally occurring truncations. We recently showed that the activity of PSMα3, the most toxic member, stems from the formation of cross-α fibrils, which are at variance with the cross-β fibrils linked with eukaryotic amyloid pathologies. Here, we show that PSMα1 and PSMα4, involved in biofilm structuring, form canonical cross-β amyloid fibrils wherein β-sheets tightly mate through steric zipper interfaces, conferring high stability. Contrastingly, a truncated PSMα3 has antibacterial activity, forms reversible fibrils, and reveals two polymorphic and atypical β-rich fibril architectures. These architectures are radically different from both the cross-α fibrils formed by full-length PSMα3, and from the canonical cross-β fibrils. Our results point to structural plasticity being at the basis of the functional diversity exhibited by S. aureus PSMαs.

scholarly journals Staphylococcus aureus PSMα3 Cross-α Fibril Polymorphism and Determinants of Cytotoxicity

2018 ◽  
Author(s):  
Einav Tayeb-Fligelman ◽  
Nir Salinas ◽  
Orly Tabachnikov ◽  
Meytal Landau
Keyword(s):  
Staphylococcus Aureus ◽  
Dynamic Process ◽  
Electrostatic Interactions ◽  
Amyloid Fibrils ◽  
List Type ◽  
Peptide Family ◽  
The Family ◽  
The Cross ◽  
Structure Switching

SummaryThe phenol-soluble modulin (PSM) peptide family, secreted by Staphylococcus aureus, performs various virulence activities, some mediated by the formation of amyloid fibrils of diverse architectures. Specifically, PSMα1 and PSMα4 structure the S. aureus biofilm by assembling into robust cross-β amyloid fibrils. PSMα3, the most cytotoxic member of the family, assembles into cross-α fibrils in which α-helices stack into tightly mated sheets, mimicking the cross-β architecture. Here we demonstrated that massive T-cell deformation and death is linked with PSMα3 aggregation and co-localization with cell membranes. Our extensive mutagenesis analyses supported the role of positive charges, and especially Lys17, in interactions with the membrane, and suggested their regulation by inter- and intra-helical electrostatic interactions within the cross-α fibril. We hypothesize that PSMα3 cytotoxicity is governed by the ability to form cross-α fibrils and involves a dynamic process of co-aggregation with cell membrane, rupturing it.HighlightsThe cytotoxic S. aureus PSMα3 assembles into cross-α fibrilsCross-α fibril polymorphism and mutations-induced secondary structure switchingRegulation by cross-α fibril inter- and intra-helical electrostatic interactionsToxicity as a putative dynamic process of PSMα3 co-aggregation with membranes

scholarly journals The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

2021 ◽  
Vol 118 (3) ◽  
pp. e2014442118
Author(s):  
Nir Salinas ◽  
Einav Tayeb-Fligelman ◽  
Massimo D. Sammito ◽  
Daniel Bloch ◽  
Raz Jelinek ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Membrane Damage ◽  
Fibril Formation ◽  
Regulation Mechanism ◽  
Bacterial Cells ◽  
Amyloid Fibril Formation ◽  
Β Amyloid ◽  
Β Sheets

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.

A Buried Glutamate in the Cross-β Core Renders β-endorphin Fibrils Reversible

Nanoscale ◽  
2021 ◽  
Author(s):  
Yuying Liu ◽  
Yu Zhang ◽  
Yunxiang Sun ◽  
Feng Ding
Keyword(s):  
Biological Functions ◽  
Naturally Occurring ◽  
Irreversible Aggregation ◽  
The Cross ◽  
Living Organisms ◽  
Functional Amyloids

Functional amyloids are abundant in living organisms from prokaryotes to eukaryotes playing diverse biological functions. In contrast to the irreversible aggregation of most known pathological amyloids, we postulate that naturally-occurring...

scholarly journals Nanostructure and stability of calcitonin amyloids

2017 ◽  
Vol 292 (18) ◽  
pp. 7348-7357 ◽  
Author(s):  
Federica Rigoldi ◽  
Pierangelo Metrangolo ◽  
Alberto Redaelli ◽  
Alfonso Gautieri
Keyword(s):  
Amyloid Fibrils ◽  
Md Simulations ◽  
Full Length ◽  
Structural Basis ◽  
Human Calcitonin ◽  
Nmr Data ◽  
Parallel Arrangement ◽  
Β Sheets ◽  
Α Helix ◽  
Β Sheet

Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel β-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel β-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp15 and Phe19 aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel β-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel β-sheet packing.

scholarly journals The Cryo-EM Structures of two Amphibian Antimicrobial Cross-β Amyloid Fibrils

2022 ◽  
Author(s):  
Robert Bücker ◽  
Carolin Seuring ◽  
Cornelia Cazey ◽  
Katharina Veith ◽  
Maria García-Alai ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Self Assembly ◽  
Amyloid Fibrils ◽  
Antimicrobial Properties ◽  
Low Complexity ◽  
Morphological Variations ◽  
Fibril Structure ◽  
Switch Mechanism ◽  
Β Sheets ◽  
Functional Amyloids

The amyloid-antimicrobial link hypothesis is based on antimicrobial properties found in human amyloids involved in neurodegenerative and systemic diseases, along with amyloidal structural properties found in antimicrobial peptides (AMPs) across kingdoms of life. Supporting this hypothesis, we here determined the fibril structure of two AMPs from amphibians, uperin 3.5 and aurein 3.3, by cryogenic electron microscopy (cryo-EM), revealing amyloid cross-β fibrils of mated β-sheets at atomic resolution. Uperin 3.5 displayed substantial polymorphism with a protofilament of two mated β-sheets. The determined structure was a polymorph showing a 3-blade symmetrical propeller of nine peptides per fibril layer including tight β-sheet interfaces. This cross-β cryo-EM structure complements the cross-α fibril conformation previously determined by a crystal structure, substantiating a secondary structure switch mechanism of uperin 3.5. The aurein 3.3 arrangement consisted of six peptides per fibril layer, all showing kinked β-sheets allowing a rounded compactness of the fibril. The kinked β-sheets are similar to LARKS (Low-complexity, Amyloid-like, Reversible, Kinked segments) found in human functional amyloids. The amyloidal properties of antimicrobial peptides shed light on a mechanism of regulation of animicrobial activity involving self-assembly and fibril morphological variations. Moreover, the known endurance of amyloid structures can provide a template for the design of sturdy antimicrobials.

scholarly journals The Amphibian Antimicrobial Peptide Uperin 3.5 is a Cross-α/Cross-β Chameleon Functional Amyloid

2020 ◽  
Author(s):  
Nir Salinas ◽  
Einav Tayeb-Fligelman ◽  
Massimo Sammito ◽  
Daniel Bloch ◽  
Raz Jelinek ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Membrane Damage ◽  
Fibril Formation ◽  
Regulation Mechanism ◽  
Bacterial Cells ◽  
Amyloid Fibril Formation ◽  
Β Amyloid ◽  
Β Sheets

AbstractAntimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic-resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 were comprised of parallel and anti-parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. Uperin 3.5 demonstrated chameleon properties, with a secondary structure switch to cross-β fibrils with reduced antibacterial activity in the absence of lipids or after heat shock. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.

scholarly journals Current Understanding of the Structure, Stability and Dynamic Properties of Amyloid Fibrils

2021 ◽  
Vol 22 (9) ◽  
pp. 4349
Author(s):  
Eri Chatani ◽  
Keisuke Yuzu ◽  
Yumiko Ohhashi ◽  
Yuji Goto
Keyword(s):  
Amyloid Fibrils ◽  
Polypeptide Chain ◽  
Dynamic Properties ◽  
Protein Molecule ◽  
Side Chain ◽  
Structure Stability ◽  
Side Chains ◽  
Precise Control ◽  
Functional Amyloids ◽  
Structural Architecture

Amyloid fibrils are supramolecular protein assemblies represented by a cross-β structure and fibrous morphology, whose structural architecture has been previously investigated. While amyloid fibrils are basically a main-chain-dominated structure consisting of a backbone of hydrogen bonds, side-chain interactions also play an important role in determining their detailed structures and physicochemical properties. In amyloid fibrils comprising short peptide segments, a steric zipper where a pair of β-sheets with side chains interdigitate tightly is found as a fundamental motif. In amyloid fibrils comprising longer polypeptides, each polypeptide chain folds into a planar structure composed of several β-strands linked by turns or loops, and the steric zippers are formed locally to stabilize the structure. Multiple segments capable of forming steric zippers are contained within a single protein molecule in many cases, and polymorphism appears as a result of the diverse regions and counterparts of the steric zippers. Furthermore, the β-solenoid structure, where the polypeptide chain folds in a solenoid shape with side chains packed inside, is recognized as another important amyloid motif. While side-chain interactions are primarily achieved by non-polar residues in disease-related amyloid fibrils, the participation of hydrophilic and charged residues is prominent in functional amyloids, which often leads to spatiotemporally controlled fibrillation, high reversibility, and the formation of labile amyloids with kinked backbone topology. Achieving precise control of the side-chain interactions within amyloid structures will open up a new horizon for designing useful amyloid-based nanomaterials.

scholarly journals Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome

Autophagy ◽  
2014 ◽  
Vol 10 (10) ◽  
pp. 1761-1775 ◽  
Author(s):  
Mi-Hyang Cho ◽  
Kwangmin Cho ◽  
Hoe-Jin Kang ◽  
Eun-Young Jeon ◽  
Hun-Sik Kim ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Amyloid Fibrils ◽  
Β Amyloid
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