Evolution of primate θ-defensins: a serpentine path to a sweet tooth

Nguyen, Tam; Cole, Alex M.; Lehrer, Robert I.

doi:10.1016/j.peptides.2003.07.023

Cited by 168 publications

(172 citation statements)

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“…The three subfamilies of defensins (␣, ␤, and ) found in mammals evolved from a common ancestral gene (10,11) whose ␤-defensin progeny extend back to bony fishes (12), if not beyond (13). All of these defensin peptides contain six cysteines, have three intramolecular disulfide bonds, and are cationic.…”

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confidence: 99%

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Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

Lehrer

Jung

Ruchala

et al. 2009

The Journal of Immunology

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Four of the six human α-defensins (human neutrophil peptides 1–3 and human α-defensin 5; HD5) have a lectin-like ability to bind glycosylated proteins. Using HD5 as a model, we applied surface plasmon resonance techniques to gain insights into this property. HD5 bound natural glycoproteins > neoglycoproteins based on BSA > nonglycosylated BSA ≫ free sugars. The affinity of HD5 for simple sugars covalently bound to BSA was orders of magnitude greater than its affinity for the same sugars in solution. The affinity of HD5 for protein-bound carbohydrates resulted from multivalent interactions which may also involve noncarbohydrate residues of the proteins. HD5 showed concentration-dependent self-association that began at submicromolar concentrations and proceeded to dimer and tetramer formation at concentrations below 5 μM. The (R9A, R28A) and (R13A, R32A) analogs of HD5 showed greatly reduced self-association as well as minimal binding to BSA and to BSA-affixed sugars. From this and other evidence, we conclude that the extensive binding of HD5 to (neo)glycoproteins results from multivalent nonspecific interactions of individual HD5 molecules with carbohydrate and noncarbohydrate moieties of the target molecule and that the primary binding events are magnified and enhanced by subsequent in situ assembly and oligomerization of HD5. Self-association and multivalent binding may play integral roles in the ability of HD5 to protect against infections caused by viruses and other infectious agents.

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confidence: 99%

“…All of these defensin peptides contain six cysteines, have three intramolecular disulfide bonds, and are cationic. To date, ␣-defensin peptides have been found only in mammals (14) and -defensins have been identified only in certain nonhuman primates (11,15,16). ␣-Defensins have a largely ␤-sheet structure composed of 29-to 35-aa residues.…”

mentioning

confidence: 99%

Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

Lehrer

Jung

Ruchala

et al. 2009

The Journal of Immunology

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“…Humans have multiple -defensin genes, including some that are transcribed. However, human genes and their transcripts contain a premature stop codon that aborts successful translation (27,31). Retrocyclins 1-3 are synthetic -defensin peptides, whose structures are based on human multiple -defensin pseudogenes.…”

mentioning

confidence: 99%

Retrocyclins Kill Bacilli and Germinating Spores of Bacillus anthracis and Inactivate Anthrax Lethal Toxin

Wang

Mulakala

Ward

et al. 2006

Journal of Biological Chemistry

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-defensins are cyclic octadecapeptides encoded by the modified ␣-defensin genes of certain nonhuman primates. The recent demonstration that human ␣-defensins could prevent deleterious effects of anthrax lethal toxin in vitro and in vivo led us to examine the effects of -defensins on Bacillus anthracis (Sterne). We tested rhesus -defensins 1-3, retrocyclins 1-3, and several analogues of RC-1. Low concentrations of -defensins not only killed vegetative cells of B. anthracis (Sterne) and rendered their germinating spores nonviable, they also inactivated the enzymatic activity of anthrax lethal factor and protected murine RAW-264.7 cells from lethal toxin, a mixture of lethal factor and protective antigen. Structure-function studies indicated that the cyclic backbone, intramolecular tri-disulfide ladder, and arginine residues of -defensins contributed substantially to these protective effects. Surface plasmon resonance studies showed that retrocyclins bound the lethal factor rapidly and with high affinity. Retrocyclin-mediated inhibition of the enzymatic activity of lethal factor increased substantially if the enzyme and peptide were preincubated before substrate was added. The temporal discrepancy between the rapidity of binding and the slowly progressive extent of lethal factor inhibition suggest that post-binding events, perhaps in situ oligomerization, contribute to the antitoxic properties of retrocyclins. Overall, these findings suggest that -defensins provide molecular templates that could be used to create novel agents effective against B. anthracis and its toxins.Under normal circumstances Bacillus anthracis causes human infections only in individuals exposed to infected farm animals or their spore-contaminated products. The virulence of B. anthracis primarily derives from the hardiness of its spores, an anti-phagocytic capsule that surrounds its vegetative cells (1), and two secreted binary toxins: lethal toxin (LeTx) 3 and edema toxin (EdTx). Both toxins contain protective antigen (PA, 83 kDa). LeTx also contains lethal factor (LF, 90 kDa), and EdTx contains edema factor (EF, 89 kDa). The genes for all three toxin components, PA, LF, and EF, reside on the pXO1 plasmid (2), and those responsible for capsule synthesis exist on the pXO2 plasmid (3). Both of these plasmids are required for in vivo virulence (3).EF is an adenylate cyclase (4) and LF is a zinc-dependent metalloprotease that selectively attacks certain MAPK kinases (5, 6). PA is required to allow both of the other toxin components to enter host cells (7). When PA binds a cellular receptor (8), it is cleaved into PA63 (63 kDa) and PA20 (20 kDa). The PA20 diffuses away, and the residual receptor-bound PA63 molecules self-associate into ring-shaped heptamers (9) that bind EF or LF with high affinity (10 -12). Oligomerization of PA63 leads to endocytosis, which transports the complexes to an acidic compartment (13-15). Here, the heptameric pre-pore changes into an integral-membrane pore (16, 17) that translocates EF or LF into the cytosol (18). Immu...

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“…In humans, 6 α-defensins have been identified: human neutrophil peptide (HNP) -1 to -4 that are found in the azurophilic granules of neutrophils 7) , and human defensin (HD) -5 and -6 that are abundantly expressed in the Paneth cells of the small intestine 8) 9) . The θ-defensins are found in the neutrophils of"old world" non-human primates such as the gorilla and chimpanzee, but have not been identified in humans 10) . To date, six different hBDs have been identified and characterized in humans.…”

Section: Human β-Defensins (Hbds)mentioning

confidence: 99%

Novel Insight Into the Role of Antimicrobial (Host Defense) Peptides/Proteins in Human Skin Diseases

Niyonsaba

2016

Juntendo Medical Journal

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In addition to functioning as a physical barrier, the skin has evolved several innate defense mechanisms for the rapid recognition of and protection against harmful microorganisms. As a part of this process, the skin releases a vast and powerful arsenal of antimicrobial peptides/proteins (AMPs), also called host defense peptides/proteins (HDPs), which are key players in the cutaneous immune system. Although originally named antimicrobial peptides, recent evidence has demonstrated that AMPs/HDPs play additional roles in orchestrating the adaptive immune response, such as the regulation of inflammation, induction of cell proliferation and differentiation, regulation of cytokine/chemokine production, facilitation of cell migration, promotion of wound healing and regulation of tight junction barriers. Additionally, numerous skin diseases show altered expression of AMPs/HDPs in the lesional skin, suggesting the crucial roles of these molecules in the pathophysiology of skin diseases. The purpose of this review is to describe the current knowledge regarding some of the most common and well-known AMPs/HDPs derived from the skin, to discuss the regulation of their expression and their antimicrobial and immunomodulatory functions, and to outline their roles in various skin diseases. We believe that understanding the basic knowledge of skin-derived AMPs/HDPs would provide new insight into the pathophysiology of skin disorders and offer novel therapeutic opportunities for skin infectious diseases.

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Evolution of primate θ-defensins: a serpentine path to a sweet tooth

Cited by 168 publications

References 37 publications

Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

Retrocyclins Kill Bacilli and Germinating Spores of Bacillus anthracis and Inactivate Anthrax Lethal Toxin

Novel Insight Into the Role of Antimicrobial (Host Defense) Peptides/Proteins in Human Skin Diseases

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