Current Protein and Peptide Science - Volume 9, Issue 6, 2008

Gelsolin is a highly conserved, multifunctional actin-binding protein initially described in the cytosol of macrophages and subsequently identified in many vertebrate cells. A unique property of gelsolin is that in addition to its widely recognized function as a cytoplasmic regulator of actin organization, the same gene expresses a splice variant coding for a distinct isoform, plasma gelsolin, which is secreted into extracellular fluids. The secreted form of gelsolin has been implicated in a number of processes such as the extracellular actin scavenging system and the presentation of lysophosphatidic acid and other inflammatory mediators to their receptors, in addition to its function as a substrate for extracellular matrix-modulating enzymes. Consistent with these proposed functions, blood gelsolin levels decrease markedly in a variety of clinical conditions such as acute respiratory distress syndrome, sepsis, major trauma, prolonged hyperoxia, malaria, and liver injury. This correlation between blood gelsolin levels and critical clinical conditions suggests the potential utility of gelsolin as a prognostic marker as well as the possibility for therapeutic replenishment of gelsolin to alleviate the injurious cascades in these settings. This review summarizes current data supporting a role of plasma gelsolin in extracellular fluids and the potential for its use as a diagnostic marker or therapeutic treatment in several medical conditions.

Heat shock proteins (Hsps) are molecular chaperones that oppose stress-induced denaturation of other proteins. Hsps are present in all organisms. Apart from assisting in the efficient folding of newly synthesized proteins they maintain pre-existing proteins in a stable conformation, preventing their aggregation, under stress conditions. The latter role, essential for thermal adaptation, requires that the chaperone system change from a folding to a storing function at heat shock temperatures. The temperature at which this change occurs depends on the presence of a thermosensor in at least one of the components of the chaperone systems. In this review, we focus on the bacterial GroE and DnaK systems, describe their temperature-sensitive protein components, and the location of the thermosensor within the structure of these components. While the thermosensor of the GroE system is located at the inter-ring interface of GroEL, that of the DnaK system occurs in its co-chaperone GrpE. Analysis of these examples demonstrates the amazing mechanistic diversity of thermal stress adaptation and of functional convergence of structurally unrelated proteins.

Three dimensional protein structures are crucial for understanding biology at both molecular and system level. Despite the advances in experimental structural biology, the pace of sequence deposition into databanks considerably exceeds that of structure determination. Inevitably the functional annotation of genes and genomes requires the exploitation of bioinformatics methods for protein sequence comparison and structure prediction. Hence monitoring objectively the state of art of the field is of paramount importance, in order to make best use of computational protein models to address biological questions. This review describes some relevant issues in the field of structural bioinformatics, emphasizig both open basic questions and the progress being continuously achieved. It is reasonably expected that these bioinformatics methods will increasingly contribute to the biomedical, pharmaceutical and biotechnological research.

Fishes thriving in polar habitats offer many opportunities for comparative approaches to understanding protein adaptations to temperature. Notothenioidei, the dominant suborder in the Antarctic Ocean, have evolved reduction of hemoglobin concentration and multiplicity, perhaps as a consequence of temperature stability and other environmental parameters. In the icefish family, the blood pigment is absent. In contrast, similar to other acanthomorph teleosts, Arctic fish, thriving in a more complex oceanographic system, have maintained higher hemoglobin multiplicity and a highly diversified globin system in response to environmental variability and/or variations in metabolic demands. This review summarises the current knowledge on the structure, function and phylogeny of hemoglobins of fish living in polar habitats. On the basis of crystallographic analysis, a novel guideline to the interpretation of the Root effect in terms of a threestate model is suggested, implying the accessibility of an R/T intermediate quaternary structure, frequently observed in Antarctic fish hemoglobins. The occurrence of bis-histidyl and penta-coordinate states in ferric forms of polar fish hemoglobins suggests additional redox properties.

Tandem repeats occur in 14&percnt of all proteins. The repeat unit lengths range from a single amino acid to more than 100 residues and the repeat number is sometimes over 100. Understanding the structures, functions, and evolution of these repeats is a significant goal in both proteomics and genomics. This review summarizes experimental studies addressing structural features of tandem repeats of short oligopeptides that are rich in proline, glycine, asparagine, serine, and/or threonine. The oligopetides include (PGMG) and (PNN) in biomineralization protein (PM27), and (NPNA) in Plasmodium falciparum circumsporozoite protein, (YSPTSPS) in RNA polymerase II, (PHGGGWGQ) in the prion protein, (YGHGGG(N)) and (YNHGGG(G)) in plant glycine-rich proteins, (PGQGQQ), (PGQGQQGQQ) and (GYYPTSOQQ) of wheat HMW glutenin, (FGGMGGGKGG) in Aequipecten abductin. Spectroscopic studies including NMR and CD indicate that these peptides adopt type I and II β-turns, polyproline II helices, loop conformations, and random coils. Formation of these structures frequently depends on pH, solvent, temperature and hydration. The loop conformations are sometimes stabilized by cation-π, CH-π, and/or amino-aromatic interactions. These observations indicate that many tandem repeats are largely flexible. In addition to generating repeating domains and providing flexible linkers between domains, the tandem repeats of (PHGGGWGQ), (YGHGGG(N)) and (YNHGGG(G)) and those in titin bind Cu²⁺ ions; whereas, tandem repeats of (NPNA) and those in elastin bind Ca²⁺ ions. The interactions of some tandem repeats with various target proteins probably involve an induced fit. The tandem repeats in tropoelastin, flagelliform silk, wheat HMW glutenin, abductin, titin, and human nucleoporin, nup153, are responsible for elastomeric properties.

Intrinsically disordered proteins (IDPs) represent an emerging class of proteins (or domains) that are characterized by a lack of ordered secondary and tertiary structure. This group of proteins has recently attracted tremendous interest primarily because of a unique feature: they can bind to different targets due to their structural plasticity, and thus fulfill diverse functions. The inhibitory γ-subunit (PDEγ) of retinal PDE6 is an intriguing IDP, of which unique protein properties are being uncovered. PDEγ critically regulates the turn on as well as the turn off of visual signaling through alternate interactions with the PDE6 catalytic core, transducin, and the regulator of G protein signaling RGS9-1. The intrinsic disorder of PDEγ does not compromise, but rather, optimizes its functionality. PDEγ “curls up” when free in solution but “stretches out” when binding with the PDE6 catalytic core. Conformational changes of PDEγ also likely occur in its Cterminal PDE6-binding region upon interacting with transducin during PDE6 activation. Growing evidence shows that PDEγ is also a player in non-phototransduction pathways, suggesting additional protein targets. Thus, PDE?? is highly likely to be adaptive in its structure and function, hence a “chameleon”.

The first comprehensive studies on the structure and thermodynamics of membrane proteins have started revealing the exact architecture of these macromolecules and the physical-chemical rules behind their structures. In this review, the stabilities of several families of membrane proteins, obtained by using spectroscopic, calorimetric and single molecule techniques are surveyed. The data on the stability of membrane proteins are compared with those obtained in soluble proteins. The comparison indicates that although the number of particular atomic interactions is larger in membrane proteins than in soluble ones, the overall values are similar. The consensus is that some intrinsic properties of membrane proteins resemble those of soluble ones, but there are critical differences arising form the inter-molecular contacts with the surrounding membrane. Taken together, all these efforts improve our understanding of the universal forces governing protein folding, and will help in the design of membrane proteins in the near future.

The peptide hormone relaxin (RLX) has been shown to exert a variety of functions in both reproductive and non-reproductive tissues. The molecular mechanism of RLX on its target cells appears to involve multiple intracellular signalling systems, including the nitric oxide (NO) pathway. NO is an ubiquitous molecule synthesised from L-arginine under the catalytic action of different nitric oxide synthase (NOS) isoforms and its altered production has been reported to be involved in several diseases. RLX has been demonstrated to promote NO biosynthesis by up-regulating NOS expression; its influence on the different NOS appears to depend on the cell type studied. In addition to its physiological roles, RLX has been postulated as a potential therapeutic agent in several diseases. In particular, based on its property to promote NO biosynthesis, RLX may be regarded as a therapeutic tool in diseases characterized pathogenically by an impaired NO production. The aim of the present mini-review is to summarize and discuss the pathophysiological actions of RLX, strictly related to its ability to activate the endogenous NO pathway in reproductive and non-reproductive target organs.