Antimicrobial Protegrin-1 Forms Amyloid-Like Fibrils with Rapid Kinetics Suggesting a Functional Link

Jang, Hyunbum; Arce, Fernando Terán; Mustata, Mirela; Ramachandran, Srinivasan; Capone, Ricardo; Nussinov, Ruth; Lal, Ratnesh

doi:10.1016/j.bpj.2011.01.072

Cited by 122 publications

(129 citation statements)

References 66 publications

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“…Interestingly, other amyloidogenic peptides such as amyloid-␤ and protegrin-1 (6)(7)(8) have been shown to have bactericidal properties, which are thought to be mediated via a channel-forming mechanism (9). Amyloid-forming peptides have also been shown to mediate antimicrobial effects by binding and sequestering bacteria.…”

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confidence: 99%

Semen-Derived Enhancer of Viral Infection (SEVI) Binds Bacteria, Enhances Bacterial Phagocytosis by Macrophages, and Can Protect against Vaginal Infection by a Sexually Transmitted Bacterial Pathogen

Easterhoff

Ontiveros

Brooks

et al. 2013

Antimicrob Agents Chemother

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The semen-derived enhancer of viral infection (SEVI) is a positively charged amyloid fibril that is derived from a self-assembling proteolytic cleavage fragment of prostatic acid phosphatase (PAP 248-286 ). SEVI efficiently facilitates HIV-1 infection in vitro, but its normal physiologic function remains unknown. In light of the fact that other amyloidogenic peptides have been shown to possess direct antibacterial activity, we investigated whether SEVI could inhibit bacterial growth. Neither SEVI fibrils nor the unassembled PAP 248-286 peptide had significant direct antibacterial activity in vitro. However, SEVI fibrils bound to both Grampositive (Staphylococcus aureus) and Gram-negative (Escherichia coli and Neisseria gonorrhoeae) bacteria, in a charge-dependent fashion. Furthermore, SEVI fibrils but not the monomeric PAP 248-286 peptide promoted bacterial aggregation and enhanced the phagocytosis of bacteria by primary human macrophages. SEVI also enhanced binding of bacteria to macrophages and the subsequent release of bacterially induced proinflammatory cytokines (tumor necrosis factor alpha [TNF-␣], interleukin-6 [IL-6], and IL-1␤). Finally, SEVI fibrils inhibited murine vaginal colonization with Neisseria gonorrhoeae. These findings demonstrate that SEVI has indirect antimicrobial activity and that this activity is dependent on both the cationic charge and the fibrillar nature of SEVI.

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confidence: 99%

Semen-Derived Enhancer of Viral Infection (SEVI) Binds Bacteria, Enhances Bacterial Phagocytosis by Macrophages, and Can Protect against Vaginal Infection by a Sexually Transmitted Bacterial Pathogen

Easterhoff

Ontiveros

Brooks

et al. 2013

Antimicrob Agents Chemother

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“…iv) AMPs, like PG-1 and LL-37 have been reported to form fibrils under certain conditions [131,132].…”

Section: Iappmentioning

confidence: 99%

Current Understanding of the Mechanisms by which Membrane-Active Peptides Permeate and Disrupt Model Lipid Membranes

Sun

Forsman²,

Woodward

2015

CTMC

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Link to publicationCitation for published version (APA): Sun, D., Forsman, J., & Woodward, C. E. (2016). Current understanding of the mechanisms by which membrane-active peptides permeate and disrupt model lipid membranes. Current Topics in Medicinal Chemistry, 16(2), 170-186. DOI: 10.2174/1568026615666150812121241 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal translocation, but associated with this, is membrane rupture to form large pores, which are subsequently stabilized by peptide adsorption to the pore edges. This disruption to the membrane is presumably responsible for cell death. Amyloidal peptides also show evidence of stable large pore formation, however, the mechanism for pore stabilization appears linked with their ability to form fibrils and prefibrillar aggregates and oligomers. There is some evidence that pores and membrane defects in fact act as nucleation sites for these structures. Where possible we have related the experimental and theoretical work to our own simulation findings in an effort to produce a comprehensive, albeit speculative picture for the mechanisms of action for this important group of peptides. Keywords:Membrane active peptides; anti-microbial peptides; cell-penetrating peptides; amyloid peptides; lipid membrane; pore-formation 3 Graphical AbstractWe review the modes of activity of three classes of membrane active peptides: cell penetrating; antimicrobial, and amyloid peptides.4

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“…AMPs can provide a rapid response to infection and are often effective against a broad range of bacterial species (Heller et al 1998). The monomeric structures of small AMPs can be classified into several groups based on their amino acid compositions and structure (Brogden 2005;Friedrich et al 2000;Jang et al 2011;Powers and Hancock 2003;Sitaram and Nagaraj 2002;Steinberg et al 1997;Zasloff 2002). One of them adopt an a-helical structure when bound to lipid membranes, other adopt b-type structures stabilized by disulfide bonds.…”

Section: Introductionmentioning

confidence: 99%

“…Their interaction with the membrane results in permeability changes and may cause cytolysis. An AMPs cytotoxicity primarily takes place by incorporation into the membrane, ultimately disrupting its structure either by formation of pores or via alteration of the bilayer fluidity (Brogden 2005;Gottler et al 2008;Jang et al 2011Jang et al , 2008Lam et al 2006;Matsuzaki 1999;Shai 1999;Sokolov et al 1999;Yang et al 2000;Zasloff 2002).…”

Section: Introductionmentioning

confidence: 99%

“…It was shown that the b-forming PG-1 peptide exhibits amyloid-like ion channel behaviour in model lipid bilayers (Gottler et al 2008;Jang et al 2011;Sokolov et al 1999;Yang et al 2000) and PG-1 and Ab share a common cellular mechanism, such as membrane disruption and pore formation, preceded by toxic ion channel formation, leading to cell death (Jang et al 2011). PG-1 adopts a dimeric structure (PDB: 1ZY6) in dodecylphosphocholine (DPC) micelles (Aumelas et al 1996), and a channel is formed by the association of several dimers but the molecular mechanisms of the membrane damage by non-a-helical peptides are still unknown (Bechinger 2000).…”

Section: Introductionmentioning

confidence: 99%

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High-resolution NMR structure of the antimicrobial peptide protegrin-2 in the presence of DPC micelles

et al. 2014

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PG-1 adopts a dimeric structure in dodecylphosphocholine (DPC) micelles, and a channel is formed by the association of several dimers but the molecular mechanisms of the membrane damage by non-α-helical peptides are still unknown. The formation of the PG-1 dimer is important for pore formation in the lipid bilayer, since the dimer can be regarded as the primary unit for assembly into the ordered aggregates. It was supposed that only 12 residues (RGGRL-CYCRR-RFCVC-V) are needed to endow protegrin molecules with strong antibacterial activity and that at least four additional residues are needed to add potent antifungal properties. Thus, the 16-residue protegrin (PG-2) represents the minimal structure needed for broad-spectrum antimicrobial activity encompassing bacteria and fungi. As the peptide conformation and peptide-to-membrane binding properties are very sensitive to single amino acid substitutions, the solution structure of PG-2 in solution and in a membrane mimicking environment are crucial. In order to find evidence if the oligomerization state of PG-1 in a lipid environment will be the same or not for another protegrins, we investigate in the present work the PG-2 NMR solution structure in the presence of perdeuterated DPC micelles. The NMR study reported in the present work indicates that PG-2 form a well-defined structure (PDB: 2MUH) composed of a two-stranded antiparallel β-sheet when it binds to DPC micelles.

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Antimicrobial Protegrin-1 Forms Amyloid-Like Fibrils with Rapid Kinetics Suggesting a Functional Link

Cited by 122 publications

References 66 publications

Semen-Derived Enhancer of Viral Infection (SEVI) Binds Bacteria, Enhances Bacterial Phagocytosis by Macrophages, and Can Protect against Vaginal Infection by a Sexually Transmitted Bacterial Pathogen

Semen-Derived Enhancer of Viral Infection (SEVI) Binds Bacteria, Enhances Bacterial Phagocytosis by Macrophages, and Can Protect against Vaginal Infection by a Sexually Transmitted Bacterial Pathogen

Current Understanding of the Mechanisms by which Membrane-Active Peptides Permeate and Disrupt Model Lipid Membranes

High-resolution NMR structure of the antimicrobial peptide protegrin-2 in the presence of DPC micelles

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