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1.
Human skin is permanently exposed to microorganisms, but rarely infected. One reason for this natural resistance might be
the existence of a ‘chemical barrier’ consisting in constitutively and inducibly produced antimicrobial peptides and proteins
(AMPs). Many of these AMPs can be induced in vitro by proinflammatory cytokines or bacteria. Apart from being expressed in vivo in inflammatory lesions, some AMPs are also focally expressed in skin in the absence of inflammation. This suggests that
non-inflammatory stimuli of endogenous and/or exogenous origin can also stimulate AMP synthesis without inflammation. Such
mediators might be ideal ‘immune stimulants’ to induce only the innate antimicrobial skin effector molecules without causing
inflammation.
Received 9 August 2005; received after revision 21 October 2005; accepted 16 November 2005 相似文献
2.
The application of fractal dimension-based constructs to probe the protein interior dates back to the development of the concept
of fractal dimension itself. Numerous approaches have been tried and tested over a course of (almost) 30 years with the aim
of elucidating the various facets of symmetry of self-similarity prevalent in the protein interior. In the last 5 years especially,
there has been a startling upsurge of research that innovatively stretches the limits of fractal-based studies to present
an array of unexpected results on the biophysical properties of protein interior. In this article, we introduce readers to
the fundamentals of fractals, reviewing the commonality (and the lack of it) between these approaches before exploring the
patterns in the results that they produced. Clustering the approaches in major schools of protein self-similarity studies,
we describe the evolution of fractal dimension-based methodologies. The genealogy of approaches (and results) presented here
portrays a clear picture of the contemporary state of fractal-based studies in the context of the protein interior. To underline
the utility of fractal dimension-based measures further, we have performed a correlation dimension analysis on all of the
available non-redundant protein structures, both at the level of an individual protein and at the level of structural domains.
In this investigation, we were able to separately quantify the self-similar symmetries in spatial correlation patterns amongst
peptide–dipole units, charged amino acids, residues with the π-electron cloud and hydrophobic amino acids. The results revealed
that electrostatic environments in the interiors of proteins belonging to ‘α/α toroid’ (all-α class) and ‘PLP-dependent transferase-like’
domains (α/β class) are highly conducive. In contrast, the interiors of ‘zinc finger design’ (‘designed proteins’) and ‘knottins’
(‘small proteins’) were identified as folds with the least conducive electrostatic environments. The fold ‘conotoxins’ (peptides)
could be unambiguously identified as one type with the least stability. The same analyses revealed that peptide–dipoles in
the α/β class of proteins, in general, are more correlated to each other than are the peptide–dipoles in proteins belonging
to the all-α class. Highly favorable electrostatic milieu in the interiors of TIM-barrel, α/β-hydrolase structures could explain
their remarkably conserved (evolutionary) stability from a new light. Finally, we point out certain inherent limitations of
fractal constructs before attempting to identify the areas and problems where the implementation of fractal dimension-based
constructs can be of paramount help to unearth latent information on protein structural properties. 相似文献
3.
Giuliani A Pirri G Bozzi A Di Giulio A Aschi M Rinaldi AC 《Cellular and molecular life sciences : CMLS》2008,65(16):2450-2460
The innate immunity of multicellular organisms relies in large part on the action of antimicrobial peptides (AMPs) to resist microbial invasion. Crafted by evolution into an extremely diversified array of sequences and folds, AMPs do share a common amphiphilic 3-D arrangement. This feature is directly linked with a common mechanism of action that predominantly (although not exclusively) develops upon interaction of peptides with cell membranes of target cells. This minireview reports on current understanding of the modes of interaction of AMPs with biological and model membranes, especially focusing on recent insights into the folding and oligomerization requirements of peptides to bind and insert into lipid membranes and exert their antibiotic effects. Given the potential of AMPs to be developed into a new class of anti-infective agents, emphasis is placed on how the information on peptide-membrane interactions could direct the design and selection of improved biomimetic synthetic peptides with antibiotic properties. 相似文献
4.
Stec B 《Cellular and molecular life sciences : CMLS》2006,63(12):1370-1385
Thionins belong to a rapidly growing family of biologically active peptides in the plant kingdom. Thionins are small (∼5 kDA),
cysteine-rich peptides with toxic and antimicrobial properties. They show a broad cellular toxicity against wide range of
organisms and eukaryotic cell lines; while possessing some selectivity. Thionins are believed to be involved in protection
against plant pathogens, including bacteria and fungi, by working directly at the membrane. The direct mechanism of action
is still surrounded by controversy. Here the results of structural studies are reviewed and confronted with recent results
of biophysical studies aimed at defining the function of thionins. The proposed toxicity mechanisms are reviewed and the attempt
to reconcile competing hypotheses with a wealth of structural and functional studies is made.
Received 3 December 2005; received after revision 6 February 2006; accepted 18 March 2006 相似文献
5.
Conlon JM 《Cellular and molecular life sciences : CMLS》2011,68(13):2303-2315
Cationic peptides that adopt an amphipathic α-helical conformation in a membrane-mimetic environment are synthesized in the
skins of many frog species. These peptides often display cytolytic activities against bacteria and fungi consistent with the
idea that they play a role in the host’s system of defense against pathogenic microorganisms, but their importance in the
survival strategy of the animal is not clearly understood. Despite the common misconception that antimicrobial peptides are
synthesized in the skins of all anurans, the species distribution is sporadic, suggesting that their production may confer
some evolutionary advantage to the organism but is not necessary for survival. The low potency of many frog skin antimicrobial
peptides is consistent with the hypothesis that cutaneous symbiotic bacteria may provide the major system of defense against
pathogenic microorganisms in the environment with antimicrobial peptides assuming a supplementary role in some species. 相似文献
6.
Nicole L. van der Weerden Mark R. Bleackley Marilyn A. Anderson 《Cellular and molecular life sciences : CMLS》2013,70(19):3545-3570
Antimicrobial peptides are a vital component of the innate immune system of all eukaryotic organisms and many of these peptides have potent antifungal activity. They have potential application in the control of fungal pathogens that are a serious threat to both human health and food security. Development of antifungal peptides as therapeutics requires an understanding of their mechanism of action on fungal cells. To date, most research on antimicrobial peptides has focused on their activity against bacteria. Several antimicrobial peptides specifically target fungal cells and are not active against bacteria. Others with broader specificity often have different mechanisms of action against bacteria and fungi. This review focuses on the mechanism of action of naturally occurring antifungal peptides from a diverse range of sources including plants, mammals, amphibians, insects, crabs, spiders, and fungi. While antimicrobial peptides were originally proposed to act via membrane permeabilization, the mechanism of antifungal activity for these peptides is generally more complex and often involves entry of the peptide into the cell. 相似文献
7.
The ATP-binding cassette family is one of the largest groupings of membrane proteins, moving allocrites across lipid membranes,
using energy from ATP. In bacteria, they reside in the inner membrane and are involved in both uptake and export. In eukaryotes,
these transporters reside in the cell’s internal membranes as well as in the plasma membrane and are unidirectional—out of
the cytoplasm. The range of substances that these proteins can transport is huge, which makes them interesting for structure–function
studies. Moreover, their abundance in nature has made them targets for structural proteomics consortia. There are eight independent
structures for ATP-binding cassette transporters, making this one of the best characterised membrane protein families. Our
understanding of the mechanism of transport across membranes and membrane protein structure in general has been enhanced by
recent developments for this family. 相似文献
8.
With the rapid rise in the emergence of bacterial strains resistant to multiple classes of antimicrobial agents, there is
an urgent need to develop novel antimicrobial therapies to combat these pathogens. Cationic host defence peptides (HDPs) and
synthetic derivatives termed innate defence regulators (IDRs) represent a promising alternative approach in the treatment
of microbial-related diseases. Cationic HDPs (also termed antimicrobial peptides) have emerged from their origins as nature’s
antibiotics and are widely distributed in organisms from insects to plants to mammals and non-mammalian vertebrates. Although
their original and primary function was proposed to be direct antimicrobial activity against bacteria, fungi, parasites and/or
viruses, cationic HDPs are becoming increasingly recognized as multifunctional mediators, with both antimicrobial activity
and diverse immunomodulatory properties. Here we provide an overview of the antimicrobial and immunomodulatory activities
of cationic HDPs, and discuss their potential application as beneficial therapeutics in overcoming infectious diseases. 相似文献
9.
Alzheimer’s disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid
beta peptide (Aβ) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared
spectroscopy to provide structural information on the entire aggregation pathway of Aβ(1–40), starting from monomeric Aβ to
the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition
from antiparallel to parallel β-sheet. These structural changes are described in terms of H-bonding rupture/formation, β-strands
reorientation and β-sheet elongation. As antiparallel β-sheet structure is also observed for other amyloidogenic proteins
forming oligomers, reorganization of the β-sheet implicating a reorientation of β-strands could be a generic mechanism determining
the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could
be essential in a search for therapies inhibiting aggregation or disrupting aggregates. 相似文献
10.
The short proline-rich antibacterial peptide family 总被引:16,自引:0,他引:16
Otvos L 《Cellular and molecular life sciences : CMLS》2002,59(7):1138-1150
From the many peptide families that are induced upon bacterial infection and can be isolated from all classes of animals,
the short, proline-rich antibacterial peptides enjoy particular interest. These molecules were shown to inactivate an intracellular
biopolymer in bacteria without destroying or remaining attached to the bacterial cell membrane, and as such emerged as viable
candidates for the treatment of mammalian infections. These peptides were originally isolated from insects, they kill mostly
Gram-negative bacteria with high efficiency and they show structural similarities with longer insect- and mammal-derived antimicrobial
peptides. However, while the distant relatives appear to carry multiple functional domains, apidaecin, drosocin, formaecin
and pyrrhocoricin consist of only minimal determinants needed to penetrate across the cell membrane and bind to the target
biopolymer. These peptides appear to inhibit metabolic processes, such as protein synthesis or chaperone-assisted protein
folding. Pyrrhocoricin derivatives protect mice from experimental infections in vivo, suggesting the utility of modified analogs
in the clinical setting. Sequence variations of the target protein at the peptide-binding site may allow the development of
new peptide variants that kill currently unresponsive strains or species.
Received 12 December 2001; received after revision 11 February 2002; accepted 19 February 2002 相似文献
11.
Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically
valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these
problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the
basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric
(dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some
of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for
the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic
oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug
market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens. 相似文献
12.
The Membrane Protein Data Bank (MPDB) is an online, searchable, relational database of structural and functional information
on integral, anchored and peripheral membrane proteins and peptides. Data originates from the Protein Data Bank and other
databases, and from the literature. Structures are based on X-ray and electron diffraction, nuclear magnetic resonance and
cryoelectron microscopy. The MPDB is searchable online by protein characteristic, structure determination method, crystallization
technique, detergent, temperature, pH, author, etc. Record entries are hyperlinked to the PDB and Pfam for viewing sequence,
three-dimensional structure and domain architecture, and for downloading coordinates. Links to PubMed are also provided. The
MPDB is updated weekly in parallel with the Protein Data Bank. Statistical analysis of MPDB records can be performed and viewed
online. A summary of the statistics as applied to entries in the MPDB is presented. The data suggest conditions appropriate
for crystallization trials with novel membrane proteins.
Received 3 August 2005; received after revision 18 September 2005; accepted 26 September 2005
This paper and the Membrane Protein Data Bank celebrate the 20th anniversary of the landmark paper in Nature (1985, 318: 618–624) describing the first ‘high-resolution’ three-dimensional structure of a membrane protein, the photosynthetic reaction
center from Rhodopseudomonas (Blastochloris) viridis. 相似文献
13.
Delivery of macromolecules into living cells by arginine-rich cell penetrating peptides (AR-CPPs) is an important new avenue
for the development of novel therapeutic strategies. However, to date the mechanism of this delivery remains elusive. Recent
data implicate endocytosis in the internalization of AR-CPPs and their macromolecular cargo and also indicate limited delivery
of macromolecules into the cell cytoplasm and nucleus. Different types of endocytosis – clathrin-dependent endocytosis, raft/caveolin-dependent
endocytosis and macropinocytosis – are all implicated in the uptake of AR-CPPs and their cargo into different cells. Cationic
AR-CPPs dramatically increase uptake of conjugated molecules through efficient binding to surface proteoglycans. Whether this
increase in binding can assure delivery of a sufficient amount of functionally active macromolecules into the cytoplasm and
nucleus or whether there is a specific mechanism by which AR-CPPs facilitate the escape of conjugated cargo from endosomes
remains to be understood.
Received 30 June 2005; received after revision 9 August 2005; accepted 30 August 2005 相似文献
14.
Diego-García E Abdel-Mottaleb Y Schwartz EF de la Vega RC Tytgat J Possani LD 《Cellular and molecular life sciences : CMLS》2008,65(1):187-200
Among the scorpion venom components whose function are poorly known or even show contrasting pharmacological results are those
called “orphan peptides”. The most widely distributed are named β-KTx or scorpine-like peptides. They contain three disulfide
bridges with two recognizable domains: a freely moving N-terminal amino acid sequence and a tightly folded C-terminal region
with a cysteine-stabilized α/β (CS-αβ) motif. Four such peptides and three cloned genes are reported here. They were assayed
for their cytolytic, antimicrobial and K
+ channel-blocking activities. Two main characteristics were found: the existence of an unusual structural and functional diversity,
whereby the full-length peptide can lyse cells or kill microorganisms, and a C-terminal domain containing the CS-αβ motif
that can block K
+ channels. Furthermore, sequence analyses and phylogenetic reconstructions are used to discuss the evolution of this type
of peptide and to highlight the versatility of the CS-αβ structures.
Received 13 August 2007; received after revision 30 October 2007; accepted 2 November 2007 相似文献
15.
Antimicrobial agents are toxic to bacteria by a variety of mechanisms. One mechanism that is very dependent on the lipid composition of the bacterial membrane is the clustering of anionic lipid by cationic antimicrobial agents. Certain species of oligo-acyl-lysine (OAK) antimicrobial agents are particularly effective in clustering anionic lipids in mixtures mimicking the composition of bacterial membranes. The clustering of anionic lipids by certain cationic antimicrobial agents contributes to the anti-bacterial action of these agents. Bacterial membrane lipids are a determining factor, resulting in some species of bacteria being more susceptible than others. In addition, lipids can be used to increase the effectiveness of antimicrobial agents when administered in vivo. Therefore, we review some of the structures in which lipid mixtures can assemble, to more effectively be utilized as antimicrobial delivery systems. We describe in more detail the complexes formed between mixtures of lipids mimicking bacterial membranes and an OAK and their usefulness in synergizing with antibiotics to overcome bacterial multidrug resistance. 相似文献
16.
In the last decade intensive research has been conducted to determine the role of innate immunity host defense peptides (also termed antimicrobial peptides) in the killing of prokaryotic and eukaryotic cells. Many antimicrobial peptides damage the cellular membrane as part of their killing mechanism. However, it is not clear what makes cancer cells more susceptible to some of these peptides, and what the molecular mechanisms underlying these activities are. Two general mechanisms were suggested: (i) plasma membrane disruption via micellization or pore formation, and (ii) induction of apoptosis via mitochondrial membrane disruption. To be clinically used, these peptides need to combine high and specific anticancer activity with stability in serum. Although so far very limited, new studies have paved the way for promising anticancer host defense peptides with a new mode of action and with a broad spectrum of anticancer activity. 相似文献
17.
The skin is our primary shield against microbial pathogens and has evolved innate and adaptive strategies to enhance immunity
in response to injury or microbial insult. The study of antimicrobial peptide (AMP) production in mammalian skin has revealed
several of the elegant strategies that AMPs use to prevent infection. AMPs are inducible by both infection and injury and
protect the host by directly killing pathogens and/or acting as multifunctional effector molecules that trigger cellular responses
to aid in the anti-infective and repair response. Depending on the specific AMP, these molecules can influence cytokine production,
cell migration, cell proliferation, differentiation, angiogenesis and wound healing. Abnormal production of AMPs has been
associated with the pathogenesis of several cutaneous diseases and plays a role in determining a patient’s susceptibility
to pathogens. This review will discuss current research on the regulation and function of AMPs in the skin and in skin disorders. 相似文献
18.
Toniolo C Crisma M Formaggio F Peggion C Epand RF Epand RM 《Cellular and molecular life sciences : CMLS》2001,58(9):1179-1188
Lipopeptaibols are members of a novel group of naturally occurring, short peptides with antimicrobial activity, characterized
by a lipophilic acyl chain at the N-terminus, a high content of the turn/helix forming α-aminoisobutyric acid and a 1,2-amino alcohol at the C-terminus. The amino acid sequences range from 6 to 10 residues and
the fatty acyl moieties from 8 to 15 carbon atoms. The peptide portion of lipopeptaibols can be shorter than those of the
nonlipidated peptaibols that range from 10 to 19 amino acid residues. The longest peptides fold into a mixed 310/α helix, whereas the shortest peptides tend to adopt a β-turn/sheet structure. Using solution methodologies, a series of analogues of trichogin GA IV was synthesized which allowed
determination of the minimal lipid chain and peptide main-chain lengths for the onset of membrane activity and exploitation
of a number of spectroscopic techniques aimed at determining its preferred conformation under a variety of conditions and
investigating in detail its mode of interaction with, and its effect on, the phospholipid membranes.
Received 26 January 2001; received after revision 7 March 2001; accepted 15 March 2001 相似文献
19.
Antifungal proteins: targets,mechanisms and prospective applications 总被引:15,自引:2,他引:13
All organisms have evolved several defence systems in order to protect themselves against bacteria, fungi and viruses. Higher organisms have developed a complex network of humoral and cellular responses, called adaptive immunity. A second defence system, innate immunity, was discovered in the early 1980s, consisting of small cationic peptides with a broad antimicrobial spectrum. These proteins act immediately at sites of infection or inflammation. The production of proteins with antimicrobial activity was not limited to higher organisms but was also found in insects, plants and microorganisms. During the last 2decades a broad range of proteins with very different structural features have been isolated and characterised from differing organisms ranging from bacteria to human beings. Over 500cationic membrane-acting proteins with antimicrobial and antifungal activities have been identified to date. Apart from these proteins, a very large number of antifungal proteins active on the fungal cell wall, on enzymes of the cell wall synthesis machinery, the plasma membrane and on intracellular targets have been characterised.Received 17 June 2003; received after revision 4 August 2003; accepted 18 August 2003 相似文献
20.
Born WK Zhang L Nakayama M Jin N Chain JL Huang Y Aydintug MK O'Brien RL 《Cellular and molecular life sciences : CMLS》2011,68(14):2335-2343
γδ T cells express adaptive antigen receptors encoded by rearranging genes. Their diversity is highest in the small region
of TCR V–J junctions, especially in the δ chain, which should enable the γδ TCRs to distinguish differences in small epitopes.
Indeed, recognition of small molecules, and of an epitope on a larger protein has been reported. Responses to small non-peptides
known as phospho-antigens are multi-clonal yet limited to a single γδ T cell subset in humans and non-human primates. Responses
to small peptides are multi-clonal or oligo-clonal, include more than one subset of γδ T cells, and occur in rodents and primates.
However, less effort has been devoted to investigate the peptide responses. To settle the questions of whether peptides can
be ligands for the γδ TCRs, and whether responses to small peptides might occur normally, peptide binding will have to be
demonstrated, and natural peptide ligands identified. 相似文献