Current Protein and Peptide Science - Volume 5, Issue 1, 2004

During the course of infection, a subset of HIV-1 proteins interacts with multiple cellular partners, sometimes in a hierarchical or sequential way. These proteins include those associated with the initial infection event, with the preparation of the cell for the replicative cycle of the virus and with the exit of new virions from the infected cell. It appears that the interactions of viral proteins with multiple cellular partners are mediated by the occurrence of ligand-induced conformational changes that direct the binding of these proteins to subsequent partners. Two of the most studied HIV-1 proteins that are known to interact with different cellular partners are gp120 and Nef. Here we discuss the interactions of these two proteins with their cellular partners and present new results indicating that the conformational changes undergone by these proteins define a novel allosteric paradigm. In the traditional view, conformational changes are thought to occur between well defined structural conformations of a protein. In gp120 and Nef, those changes involve conformations characterized by the presence of large regions devoid of stable secondary or tertiary structure. Those unstructured regions contain the binding determinants for subsequent partners and only become functionally competent by ligand-induced structuring or un-structuring of those regions. By switching binding epitopes between structured and unstructured conformations the binding affinity can be modulated by several orders of magnitude, thus effectively precluding binding against unwanted partners. A better understanding of these interactions would lead to improved strategies for inhibitor design against these viral targets.

The peptide relaxin (RLX) was one of the first hormones to be described with a specific function in parturition. In the past ten years, there has been a revaluation of RLX physiology and the concept that sex hormones play roles that are limited to reproductive functions is rapidly changing. In this view, growing evidence indicates that the peptide hormone RLX, structurally related to insulin and insulin-like growth factor and primarily secreted by the corpus luteum during pregnancy, besides well demonstrated actions on reproductive tissues, is involved in a variety of functions. Among them, RLX influences the brain and regulates pituitary hormone secretion, causes renal vasodilatation, increases coronary flow, exerts chronotropic action on the heart and affects gastrointestinal motor responses. Recent studies suggest that in several smooth muscles the hormone appears to act by promoting the biosynthesis of nitric oxide (NO), whose altered production may be involved in smooth muscle dysmotilities. The recent cloning of the RLX receptors and studies on their possible signal transduction mechanisms are stimulating researchers to further investigate the effects of this hormone and its mechanism of action. This may lead to the discovery of agonists and antagonists for RLX and the development of new therapeutic approaches in some human diseases. The aim of this mini-review is to summarize the most recent findings on the multiple actions of RLX hoping to bring a contribution for the future perspectives in this field.

The binding of amyloid beta peptides (Aβ) to plasma membranes appears to be a promising point of intervention in the events leading to the development of Alzheimer's disease (AD). This binding has been studied as regards the direct toxicity of Aβ on neurons, and the activation of a local inflammation phase involving microglia. By virtue of its structure, Aβ is able to bind to a variety of biomolecules, including lipids, proteoglycans and proteins. This review focuses on the membrane proteins that can mediate the interaction between Aβ and the plasma membranes in AD. On neurons, these are APP (amyloid precursor protein), the NMDA-R (Nmethyl- D-aspartate receptor), integrins, the β7nicotinic acetylcholine receptor (α7nAChR), the P75 neurotrophin receptor (P75NTR) and the CLAC-P / collagen type XXV (collagen-like Alzheimer amyloid plaque component precursor / collagen XXV). On glial cells, FPRL1 (formyl peptide receptor-like 1), the scavenger receptors A, BI (SR-A, SR-BI) and CD36, a complex involving CD36, α6β1-integrin and CD47, and heparan sulfate proteoglycans have been reported to bind Aβ. It should be noted that integrins, RAGE (receptor for advanced glycosylation endproducts), the Serpin-enzyme complex receptor (SEC-R) and the insulin receptor can bind Aβ and are present on neurons and on glial cells. After a presentation of the structure and the function of each of these proteins, the method used to prove their binding to Aβ is described, and the implication of this binding in AD is discussed. Finally, it is underlined that multireceptor complexes containing integrins may be involved in this interaction.

Cross-linking and cross-bridging are highly versatile methods of creating composite protein structures with desired mechanical properties such as deformation endurance, elasticity, extensibility, and stability under intensive and repetitive sheering forces. Cross-linking and crossbridging are distinguished by the bonds that hold the structural components together. Cross-linking implies a covalent association, whereas cross-bridging depends on biological recognition, in which hydrogen bonding, ionic, and hydrophobic interactions predominate. Cross-bridged structures are found in all living systems. Cytoskeletal interaction, cell invasion by pathogens, fertilization, and cellulosomal degradation of cellulose are all examples of biological processes in which cross-bridging proteins play a key role. This article will review the different types of biological cross-bridging proteins that are known and discuss their emerging nano- and biotechnological applications.

Glucagon-like peptide 2 (GLP-2) is a newly discovered gastrointestinal peptide with 33% sequence homology to glucagon. GLP-2 has attracted interest because of its potent intestinotrophic endocrine / paracrine actions. The peptide, consisting of 33-amino-acid, results from expression of the glucagon gene in the enteroendocrine L-cells of the intestinal mucosa, from where it is released mainly in response to luminal contact with unabsorbed nutrients. In addition to mucosal growth, GLP-2 enhances activities of several intestinal brush-border enzymes, and it delays gastric transit, thereby increasing the intestinal capacity for nutrient absorption. Thus, it appears that GLP-2 serves to ensure an optimal intestinal capacity. The physiological responses following exogenous administration of GLP-2 have been intensely investigated, and these appear to be rather specific for the gut, which is concordant with the localization of the GLP-2 receptor. In addition, treatment with GLP-2 in experimental animal models of several enteropathies indicates that GLP-2 ameliorates most of the observed intestinal abnormalities in these conditions. Following secretion to the blood stream, the intact peptide is degraded rather rapidly by an aminopeptidase. To circumvent the rapid and widespread metabolization of intact GLP-2, degradation-resistant synthetic GLP-2 analogues have been developed together with other approaches, such as inhibition of the GLP-2 degrading enzyme. This is of particular interest with respect to developing GLP-2 into a useful therapeutic agent in conditions with compromised intestinal function, since the first clinical trial has already indicated the potential of GLP-2 treatment in patients with short bowel syndrome.