Arginine in α-Defensins

Schmidt, Nathan W.; Tai, Kenneth P.; Kamdar, Karishma; Mishra, Abhijit; Lai, Ghee Hwee; Zhao, Kun; Ouellette, André J.; Wong, Gerard C. L.

doi:10.1074/jbc.m112.358721

Cited by 54 publications

(36 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent structural studies found a correlation between the activity of antimicrobial oligomers and their ability to form a three-dimensional, inverted hexagonal phase in mixtures with lipids. 22, 23 This highly curved phase is perhaps reminiscent of the micelle-like structures proposed in the carpet mechanism. In our view, the distinctions among pores, chaotic pores, localized carpets, and localized “hexagonal phase precursor states” are blurry.…”

Section: Introductionmentioning

confidence: 78%

“…Neither our observations nor the Monte Carlo models can distinguish a well-defined pore 14 from a chaotic pore 19 from a localized “carpet patch” 21 from a leaky hexagonal phase analogue. 22 The simulations of GFP efflux from the periplasmic space demonstrate that within a few seconds, the outer membrane acquires permeability comparable to that of a single pore of ~100 nm diameter. A toroidal pore can in principle expand to any size; in fact, micron-sized, AMP-induced pores were recently observed by AFM in a planar lipid bilayer.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Localized Permeabilization of E. coli Membranes by the Antimicrobial Peptide Cecropin A

2013

View full text Add to dashboard Cite

Fluorescence microscopy enables detailed observation of the effects of the antimicrobial peptide Cecropin A on the outer membrane (OM) and cytoplasmic membrane (CM) of single E. coli cells with sub-second time resolution. Fluorescence from periplasmic GFP decays and cell growth halts when the OM is permeabilized. Fluorescence from the DNA stain Sytox Green rises when the CM is permeabilized and the stain enters the cytoplasm. The initial membrane disruptions are localized and stable. Septating cells are attacked earlier than non-septating cells, and curved membrane surfaces are attacked in preference to cylindrical surfaces. Below a threshold bulk Cecropin A concentration, permeabilization is not observed over 30 minutes. Above this threshold, we observe a lag time of several minutes between Cecropin A addition and OM permeabilization and ~30 s between OM and CM permeabilization. The long lag times and the existence of a threshold concentration for permeabilization suggest a nucleation mechanism. However, the roughly linear dependence of mean lag time on bulk peptide concentration is not easily reconciled with a nucleation step involving simultaneous insertion of multiple peptides into the bilayer. Monte Carlo simulations suggest that within seconds the OM permeability becomes comparable to that of a pore of 100-nm diameter, or of numerous small pores distributed over a similarly large area.

show abstract

Section: Introductionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Localized Permeabilization of E. coli Membranes by the Antimicrobial Peptide Cecropin A

2013

View full text Add to dashboard Cite

show abstract

“…In previous work [10, 11] we have investigated mammalian defensins, an important class of membrane disruptive AMPs with, in vitro , broad spectrum and selective microbicidal activities against a variety of pathogens including Gram positive and Gram negative bacteria, fungi, protozoa, and enveloped viruses. Their common characteristics include molecular weights of 2–5kDa, β-strand secondary structures stabilized by conserved tri-disulfide bonds from six cysteine residues, amphipathicity, and high cationic net charge [15–17].…”

Section: Saxs Studies On Peptide-membrane Interactionsmentioning

confidence: 99%

“…Specifically, negative Gaussian membrane curvature (equivalently saddle-splay curvature) should be especially disruptive since it is topologically necessary for a variety of known membrane destabilizing processes. Our previous in vitro studies demonstrated that prototypical AMPs generated saddle-splay curvature in model membranes with physicochemical properties characteristic of bacteria membranes but not in membranes with properties that resembled eukaryotic cell plasma membranes [10, 11]. The selective generation of saddle-splay curvature in bacterial cell membranes provides AMPs with a broad mechanism to specifically target the membranes of microbes.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial peptides and induced membrane curvature: Geometry, coordination chemistry, and molecular engineering

Schmidt

Wong

2013

Current Opinion in Solid State and Materials Science

Self Cite

163

161

View full text Add to dashboard Cite

Short cationic, amphipathic antimicrobial peptides are multi-functional molecules that have roles in host defense as direct microbicides and modulators of the immune response. While a general mechanism of microbicidal activity involves the selective disruption and permeabilization of cell membranes, the relationships between peptide sequence and membrane activity are still under investigation. Here, we review the diverse functions that AMPs collectively have in host defense, and show that these functions can be multiplexed with a membrane mechanism of activity derived from the generation of negative Gaussian membrane curvature. As AMPs preferentially generate this curvature in model bacterial cell membranes, the selective generation of negative Gaussian curvature provides AMPs with a broad mechanism to target microbial membranes. The amino acid constraints placed on AMPs by the geometric requirement to induce negative Gaussian curvature are consistent with known AMP sequences. This ‘saddle-splay curvature selection rule’ is not strongly restrictive so AMPs have significant compositional freedom to multiplex membrane activity with other useful functions. The observation that certain proteins involved in cellular processes which require negative Gaussian curvature contain domains with similar motifs as AMPs, suggests this rule may be applicable to other curvature-generating proteins. Since our saddle-splay curvature design rule is based upon both a mechanism of activity and the existing motifs of natural AMPs, we believe it will assist the development of synthetic antimicrobials.

show abstract

“…However, the R/K ratio is variable, as is the number of R and K residues. R residues play an important role in modulating the activity of defensins (40)(41)(42)(43). Hence, a hybrid peptide containing the C-terminal K-rich segment of HBD-1 and the R-rich domain of -defensin was designed and synthesized.…”

Section: Resultsmentioning

confidence: 99%

A Hybrid Cationic Peptide Composed of Human β-Defensin-1 and Humanized θ-Defensin Sequences Exhibits Salt-Resistant Antimicrobial Activity

Olli

Nagaraj

Motukupally

2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We have designed a hybrid peptide by combining sequences of human ␤-defensin-1 (HBD-1) and -defensin, in an attempt to generate a molecule that combines the diversity in structure and biological activity of two different peptides to yield a promising therapeutic candidate. HBD-1 was chosen as it is a natural defensin of humans that is constitutively expressed, but its antibacterial activity is considerably impaired by elevated ionic strength. -Defensins are expressed in human bone marrow as a pseudogene and are homologous to rhesus monkey circular minidefensins. Retrocyclins are synthetic human -defensins. The cyclic nature of the -defensin peptides makes them salt resistant, nonhemolytic, and virtually noncytotoxic in vitro. However, a nonhuman circular molecule developed for clinical use would be less viable than a linear molecule. In this study, we have fused the C-terminal region of HBD-1 to the nonapeptide sequence of a synthetic retrocyclin. Cyclization was achieved by joining the terminal ends of the hybrid peptide by a disulfide bridge. The hybrid peptide with or without the disulfide bridge exhibited enhanced antimicrobial activity against both Gram-negative and Gram-positive bacteria as well as against fungi, including clinical bacterial isolates from eye infections. The peptide retained activity in the presence of NaCl and serum and was nonhemolytic in vitro. Thus, the hybrid peptide generated holds potential as a new class of antibiotics. Defensins are a group of peptides that are important components of host defense. They have the ability to recognize and neutralize invading microorganisms quickly and specifically (1-3). These peptides are diverse members of a large family of cationic host defense peptides (HDPs) that are widely distributed throughout the animal kingdom (2, 4, 5). These cysteine-rich peptides vary in their length, the spacing of their cysteine residues, and their disulfide connectivities (4, 5). Defensins show antimicrobial activities against Gram-negative and Gram-positive bacterial strains, fungi, as well as some parasites and enveloped viruses (1, 2, 4, 6). Mammalian defensins can be classified into ␣-, ␤-, and -defensins on the basis of their disulfide connectivities (2, 4, 6-8).Only ␣-and ␤-defensins are expressed in humans. -Defensin (found in rhesus monkey) displays the same connectivity associated with that of the ␣-defensins but is not functionally present in humans (7). -Defensins are much smaller (18 amino acid residues) than ␣-and ␤-defensins (29 to 45 residues), and their antiviral properties are considerably more pronounced than their antibacterial and antifungal effects (9, 10).␤-Defensins are found in epithelial cells that line mucosal surfaces and that provide the first line of defense between an organism and the environment (2, 6). To date, four human ␤-defensins (human ␤-defensin-1 [HBD-1] to HBD-4) have been characterized (5,(11)(12)(13)(14)(15)(16)(17)(18)(19). HBD-1 is expressed in epithelia that are directly exposed to the environment or microbial flora (e.g.,...

show abstract

Arginine in α-Defensins

Cited by 54 publications

References 43 publications

Localized Permeabilization of E. coli Membranes by the Antimicrobial Peptide Cecropin A

Localized Permeabilization of E. coli Membranes by the Antimicrobial Peptide Cecropin A

Antimicrobial peptides and induced membrane curvature: Geometry, coordination chemistry, and molecular engineering

A Hybrid Cationic Peptide Composed of Human β-Defensin-1 and Humanized θ-Defensin Sequences Exhibits Salt-Resistant Antimicrobial Activity

Contact Info

Product

Resources

About