Current Protein & Peptide Science

ISSN: 1389-2042

Current Protein and Peptide Science
Volume 8, Number 1, February 2007

Contents


Editorial Pp. 1


Creating Functional Artificial Proteins Pp. 3-18
Reza Razeghifard, Brett B. Wallace, Ron J. Pace and Tom Wydrzynski
[Abstract] [Full text article]


Human Rhinovirus 3C Protease as a Potential Target for the Development of Antiviral Agents Pp. 19-27
Q. May Wang and Shu-Hui Chen
[Abstract] [Full text article]


Modern Pathology: Protein Mis-Folding and Mis-Processing in Complex Disease Pp. 29-37
Ahmed Fadiel, Kenneth D. Eichenbaum, Adel Hamza, Orkon Tan, Hae H. Lee and Frederick Naftolin
[Abstract] [Full text article]


T Cell Response in Rheumatic Fever: Crossreactivity Between Streptococcal M Protein Peptides and Heart Tissue Proteins Pp. 39-44
Luiza Guilherme, Keller C. Faé, Sandra E. Oshiro, Ana C. Tanaka, Pablo M.A. Pomerantzeff and Jorge Kalil
[Abstract] [Full text article]


From Interactions of Single Transmembrane Helices to Folding of α-Helical Membrane Proteins: Analyzing Transmembrane Helix Helix Interactions in Bacteria Pp. 45-61
Dirk Schneider, Carmen Finger, Alexander Prodöhl and Thomas Volkmer
[Abstract] [Full text article]


β-Barrel Membrane Bacterial Proteins: Structure, Function, Assembly and Interaction with Lipids Pp. 63-82
Stefania Galdiero, Massimiliano Galdiero and Carlo Pedone
[Abstract] [Full text article]


Conformational Diseases and Structure-Toxicity Relationships: Lessons from Prion-Derived Peptides Pp. 83-90
Luisa Ronga, Pasquale Palladino, Susan Costantini, Angelo Facchiano, Menotti Ruvo, Ettore Benedetti, Raffaele Ragone and Filomena Rossi
[Abstract] [Full text article]


The Acute Phase Protein α1-Acid Glycoprotein: A Model for Altered Glycosylation During Diseases Pp. 91-108
Fabrizio Ceciliani and Vanessa Pocacqua
[Abstract] [Full text article]


Epitope Peptides and Immunotherapy Pp. 109-118
Soichi Tanabe
[Abstract] [Full text article]




Abstracts

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Editorial

Current Protein and Peptide Science (CPPS) begins its eighth year of publication with this issue. The past seven years have been very rewarding, with steady improvements in all aspects of publication. In mid-2006, we received word that CPPS had achieved a Citation Index of 4.15, significantly improved over the previous year’s value of 3.00. There are two reasons for the improvement in recognition of CPPS: excellent issues with great topics and excellent authors.

In the past several years, CPPS has featured a number of theme issues organized by a Guest Editor. Volume 7 featured three issues, issue 4, Immune Receptors for Glycoconjugates, Guest Editor: Dapeng Zhou, issue 5, Structure-Based Virtual Ligand Screening, Guest Editor: Bruno O. Villoutreix, and issue 6, The Multi-Purpose Amphiphilic α-Helix – A Historical Perspective, Guest Editors: David Phoenix and Fred Harris. Over the years, these special issues have attracted a considerable amount of attention, which brings citations in new publications. We will continue this feature in future issues of CPPS and welcome ideas for new special issues from the readers.

In addition to the special theme issues, the general level of the unsolicited contributions to CPPS has continued to rise. As I have stated before, it is very nice to see so many manuscripts coming from other countries around the world. As Thomas Friedman wrote, “The World is Flat”. He was referring to the fact that the internet has allowed people around the world to collaborate more easily and this is seen in science and publishing as well as in business. We continue to welcome submissions from the many scientists conducting research around the globe.


Ben M. Dunn
Distinguished Professor of Biochemistry & Molecular Biology
Editor-in-Chief
Current Protein and Peptide Science


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Creating Functional Artificial Proteins
Reza Razeghifard, Brett B. Wallace, Ron J. Pace and Tom Wydrzynski

[Full text article]

Much is now known about how protein folding occurs, through the sequence analysis of proteins of known folding geometry and the sequence/structural analysis of proteins and their mutants. This has allowed not only the modification of natural proteins but also the construction of de novo polypeptides with predictable folding patterns. Structure/function analysis of natural proteins is used to construct derived versions that retain a degree of biological activity. The constructed versions made of either natural or artificial sequences contain critical residues for activity such as receptor binding. In some cases, the functionality is introduced by incorporating binding sites for other elements, such as organic cofactors or transition metals, into the protein scaffold. While these modified proteins can mimic the function of natural proteins, they can also be constructed to have novel activities. Recently engineered photoactive proteins are good examples of such systems in which a light-induced electron transfer can be established in normally light-insensitive proteins. The present review covers some aspects of protein design that have been used to investigate protein receptor binding, cofactor binding and biological electron transfer.


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Human Rhinovirus 3C Protease as a Potential Target for the Development of Antiviral Agents
Q. May Wang and Shu-Hui Chen

[Full text article]

As the major cause of the common cold in children and adults, human rhinoviruses (HRVs) are a group of small single-stranded positive-sense RNA viruses. HRVs translate their genetic information into a polyprotein precursor that is mainly processed by a virally encoded 3C protease (3Cpro) to generate functional viral proteins and enzymes. It has been shown that the enzymatic activity of HRV 3Cpro is essential to viral replication. The 3Cpro is distinguished from most other proteases by the fact that it has a cysteine nucleophile but with a chymotrypsin-like serine protease folding. This unique protein structure together with its essential role in viral replication made the 3Cpro an excellent target for antiviral intervention. In recent years, considerable efforts have been made in the development of antiviral compounds targeting this enzyme. To further facilitate the design of potent 3C protease inhibitors for therapeutic use, this review summarizes the biochemical and structural characterization conducted on HRV 3C protease along with the recent progress on the de-velopment of 3C protease inhibitors.


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Modern Pathology: Protein Mis-Folding and Mis-Processing in Complex Disease
Ahmed Fadiel, Kenneth D. Eichenbaum, Adel Hamza, Orkon Tan, Hae H. Lee and Frederick Naftolin

[Full text article]

Electrostatic and electrochemical properties of bio-molecules, such as proteins, are governed by energy parameters that are, in part dependent on its folding. Disruption of this process can lead to the development of complex, multisystem diseases whose presentation may be organ-dependent. Examples include cystic fibrosis, alpha-1 antitrypsin deficiency, and Alzheimer disease. In addition to explaining exotic pathologic syndromes, an understanding of protein folding mechanisms may facilitate the understanding of less complex diseases and allow the development of novel therapeutic approaches.


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T Cell Response in Rheumatic Fever: Crossreactivity Between Streptococcal M Protein Peptides and Heart Tissue Proteins
Luiza Guilherme, Keller C. Faé, Sandra E. Oshiro, Ana C. Tanaka, Pablo M.A. Pomerantzeff and Jorge Kalil

[Full text article]

Molecular mimicry between streptococcal and human proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic fever (RF) and rheumatic heart disease (RHD). In this review we focus on the studies on genetic susceptibility markers involved in the development of RF/RHD and molecular mimicry mediated by T cell responses of RHD patients against streptococcal antigens and human tissue proteins. We identified several M protein epi-topes recognized by peripheral T cells of RF/RHD patients and by heart tissue infiltrating T cell clones of severe RHD patients. The regions of the M protein preferentially recognized by human T cells were also recognized by murine T cells. By analyzing the T cell receptor (TCR) we observed that some Vβ families detected on the periphery were oligoclonal expanded in the heart lesions. These results allowed us to confirm the major role of T cells in the development of RHD lesions.


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From Interactions of Single Transmembrane Helices to Folding of α-Helical Membrane Proteins: Analyzing Transmembrane Helix Helix Interactions in Bacteria
Dirk Schneider, Carmen Finger, Alexander Prodöhl and Thomas Volkmer

[Full text article]

Despite a wide variety of biological functions, α-helical membrane proteins display a rather simple transmembrane architecture. Although not many high resolution structures of transmembrane proteins are available today, our understanding of membrane protein folding has emerged in the recent years. Now we begin to develop a basic understanding of the forces that guide folding and interaction of α-helical membrane proteins. Some structural requirements for transmembrane helix interactions are defined, and common motifs have been discovered in the recent years which can drive helix-helix interactions. Nevertheless, many open questions remain to be addressed in future studies. One general problem with investigating transmembrane helix interactions is the limited number of appropriate tools, which can be applied to investigate membrane protein folding. Only recently several new techniques have been developed and established, including genetic systems, which allow measuring transmembrane helix interactions in vitro and in vivo.

In the first part of this review, we summarize several aspects of the current understanding of membrane protein folding and assembly. In the second part, we discuss genetic systems, which were developed in the recent years to measure interaction of transmembrane helices in the inner membrane of E. coli.


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β-Barrel Membrane Bacterial Proteins: Structure, Function, Assembly and Interaction with Lipids
Stefania Galdiero, Massimiliano Galdiero and Carlo Pedone

[Full text article]

Membrane proteins, although constituting about one-third of all proteins encoded by the genomes of living organisms, are still strongly underrepresented in the database of 3D protein structures, which reflects the big challenge presented by this class of proteins. Structural biologists, by employing electron and x-ray approaches, are continuously revealing new and fundamental insights into the structure, function, assembly and interaction with lipids of membrane proteins. To date, two structural motifs, α-helices and β-sheets, have been found in membrane proteins and interestingly these two structural motives correlate with the location: while α-helical bundles are most often found in the receptors and ion channels of plasma and endoplasmic reticulum membranes, β-barrels are restricted to the outer membrane of Gram-negative bacteria and in the mitochondrial membrane, and represent the structural motif used by several microbial toxins to form cytotoxic transmembrane channels. The β-barrel, while being a rigid and stable motif is a versatile scaffold, having a wide variation in the size of the barrel, in the mechanism to open or close the gate and to impose selectivity on substrates. Even if the number of x-ray structures of integral membrane proteins has greatly increased in recent years, only a few of them provide information at a molecular level on how proteins interact with lipids that surround them in the membrane. The detailed mechanism of protein lipid interactions is of fundamental importance for understanding membrane protein folding, membrane adsorption, insertion and function in lipid bilayers. Both specific and unspecific interactions with lipids may participate in protein folding and assembly.


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Conformational Diseases and Structure-Toxicity Relationships: Lessons from Prion-Derived Peptides
Luisa Ronga, Pasquale Palladino, Susan Costantini, Angelo Facchiano, Menotti Ruvo, Ettore Benedetti, Raffaele Ragone and Filomena Rossi

[Full text article]

The physiological form of the prion protein is normally expressed in mammalian cell and is highly conserved among species, although its role in cellular function remains elusive. Available evidence suggests that this protein is essential for neuronal integrity in the brain, possibly with a role in copper metabolism and cellular response to oxidative stress. In prion diseases, the benign cellular form of the protein is converted into an insoluble, protease-resistant abnormal scrapie form. This conversion parallels a conformational change of the polypeptide from a predominantly α-helical to a highly β-sheet secondary structure. The scrapie form accumulates in the central nervous system of affected individuals, and its protease-resistant core aggregates into amyloid fibrils outside the cell. The pathogenesis and molecular basis of the nerve cell loss that accompanies this process are not understood. Limited structural information is available on aggregate formation by this protein as the possible cause of these diseases and on its toxicity. A large amount of structure-activity studies is based on the prion fragment approach, but the resulting information is often difficult to untangle. This overview focuses on the most relevant structural and functional aspects of the prion-induced conformational disease linked to peptides derived from the unstructured N-terminal and globular C-terminal domains.


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The Acute Phase Protein α1-Acid Glycoprotein: A Model for Altered Glycosylation During Diseases
Fabrizio Ceciliani and Vanessa Pocacqua

[Full text article]

Glycosylation is one of the most important post-translational modifications of proteins, and has been widely acknowledged as one of the most important ways to modulate both protein function and lifespan.

The acute phase proteins are a major group of serum proteins whose concentration is altered during various pathophysi-ological conditions.

The aim of this paper is to review the structure and functions of the α1-acid glycoprotein (AGP). AGP belongs to the sub-family of immunocalins, a group of binding proteins that also have immunomodulatory functions. One of the most inter-esting features of AGP is that its glycosylation microheterogeneity can be modified during diseases. This aspect is particularly remarkable, since both the immunomodulatory and the binding properties of AGP strongly depend on its carbohydrate composition. For these reasons, AGP can be considered an outstanding model for the study of glycan pattern modification during diseases. This review is focused on the most recent studies on the occurrence of different glycoforms in plasma and tissues and how the appearance of different oligosaccharide patterns during systemic inflammation or diseases can influence AGP’s biological functions. The first part of the review will describe the structure of AGP and the several biological functions identified so far for this protein. The second part will be devoted to the post-translational modifications of the oligosaccharides micro-heterogeneity of AGP caused by pathological states. A critical evaluation of the impact of different AGP glycoforms on both its transport and anti-inflammatory features, and how the modifications of the glycan pattern can be utilized in clinical biochemistry, is also discussed.


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Epitope Peptides and Immunotherapy
Soichi Tanabe

[Full text article]

Allergic diseases affect atopic individuals, who synthesize specific Immunoglobulins E (IgE) to environmental allergens, usually proteins or glycoproteins. These allergens include grass and tree pollens, indoor allergens such as house dust mites and animal dander, and various foods.

Because allergen-specific IgE antibodies are the main effector molecules in the immune response to allergens, many stud-ies have focused on the identification of IgE-binding epitopes (called B cell epitopes), specific and minimum regions of allergen molecules that binds to IgE. Our initial studies have provided evidence that only four to five amino acid residues are enough to comprise an epitope, since pentapeptide QQQPP in wheat glutenin is minimally required for IgE binding. Afterwards, various kinds of B cell epitope structures have been clarified. Such information contributes greatly not only to the elucidation of the etiology of allergy, but also to the development of strategies for the treatment and prevention of allergy.

Allergen-specific T cells also play an important role in allergy and are obvious targets for intervention in the disease. Currently, the principle approach is to modify B cell epitopes to prevent IgE binding while preserving T cell epitopes to retain the capacity for immunotherapy. There is mounting evidence that the administration of peptide(s) containing immunodominant T cell epitopes from an allergen can induce T cell nonresponsiveness (immunotherapy). There have been clinical studies of peptide immunotherapy performed, the most promising being for bee venom sensitivity. Clinical trials of immunotherapy for cat allergen peptide have also received attention. An alternative strategy for the generation of an effective but hypoallergenic preparation for immunotherapy is to modify T cell epitope peptides by, for example, single amino acid substitution.

In this article, I will present an overview of epitopes related to allergic disease, particularly stress on allergen specific immunotherapy. In addition, our ongoing study of immunotherapy by ‘eating’ T cell epitope peptides will be described. Eating T cell epitope peptides as food provides a more practical way of inducing tolerance and a challenge to prevent allergy in daily life, as opposed to therapy by ingesting peptides as medicine.