Current Protein and Peptide Science - Volume 13, Issue 1, 2012

This issue inaugurates volume 13 of Current Protein & Peptide Science. The previous 12 volumes have achieved wide recognition by the protein and peptide research communities, as evidenced by the Impact Factor of 3.83. CPPS now publishes 8 issues per year and we expect that about half of these will be special Hot Topics issues, such as the present one. These issues are organized by a scientist who is a leader in a particular discipline within the protein and peptide science field, and this effort is acknowledged by naming the scientist Guest Editor for the issue. In the case of the present issue, Professor Vladimir Uversky of the University of South Florida serves as the Guest Editor and the issue is titled “Intrinsically Disordered Proteins”. The editorial introducing the issue follows this one. In addition to the special Hot Topics issues, we will intersperse regular issues containing manuscripts on all areas of protein and peptide science as stand-alone contributions. We welcome new submissions at all times. See the instructions to authors at http://www.benthamscience.org/cpps. In the coming months we will switch to a new and improved online submission system. Look for the announcement and new submission instructions on the Bentham Science website. As always, I am very pleased to have had the opportunity to work with so many scientists from different countries on the publication of Current Protein & Peptide Science. It has been wonderful to interact with so many scientists who are all committed to furthering our knowledge of protein structure and function. Finally, I want to thank the journal managers at Bentham Science Publishing for their tireless efforts on behalf of the journal. Best Wishes for a productive and safe New Year.

INTRODUCTION Recent bioinformatics studies revealed that proteins without stable tertiary and/or secondary structure are very common in nature [1-6]. These highly fluctuable proteins are biologically active yet fail to form specific 3D structures, existing as collapsed or extended dynamic conformational ensembles [3, 7-13]. They constitute an important addition to the protein kingdom [14], which for a long time was considered to contain globular, transmembrane, and fibrous proteins. These non-rigid, but biologically important proteins and regions are known by different names, such as pliable [15], floppy [16], rheomorphic [17], flexible [18], mobile [19], partially folded [20], natively denatured [21], natively unfolded [3, 22], natively disordered [11], intrinsically unstructured [8, 10], intrinsically denatured, [21] intrinsically unfolded [22], intrinsically disordered [9], vulnerable [23], chameleon [24], malleable [25], 4D [26], dancing proteins [27], protein clouds [12, 28], 32 proteins [24], etc. Among all these terms, the expression “intrinsically disordered protein (IDP)” is used most frequently in recent literature, and by a silent agreement is considered as the most appropriate descriptor of the phenomenon. The number of structurally and functionally characterized IDPs and proteins with disordered regions and domains is rapidly amplifying, illustrating the growing interest to this class of proteins. There are several reasons for this growing attention to IDPs. Some of them are outlined below. The first reason is the structure-function relationship. The existence of biologically active but extremely flexible proteins questions the assumption that rigid well-folded 3Dstructure is required for protein function [8-10, 12, 29]. In fact, IDPs were shown to carry out a number of crucial biological functions that are complementary to the functional repertoire of structured (ordered) proteins [9, 30-35]. Evolutionary persistence of these proteins represents strong evidence in favor of their importance and raises intriguing questions on the role of protein disorder in biological processes [7, 36]. In any given organism, IDPs constitute a unique unfoldome; i.e., a functionally broad and densely populated subset of the proteome [37-38]. IDPs are common across the three domains of life, being especially abundant in the eukaryotic proteomes [2, 6]. Signaling sequences are commonly located within regions of intrinsic disorder [5, 9, 30]. Disorder-to-order transitions in an IDP are coupled with the possibility for a single protein/region to adopt different structures in complexes with different partners [39-40]. The disorder- based signaling is modulated by various posttranslational modifications and alternative splicing [5, 41].....

Intrinsic disorder is relatively common in proteins, plays important roles in numerous cellular activities, and its prevalence was implicated in various human diseases. However, annotations of the disorder lag behind the rapidly increasing number of known protein chains. The last decade observed development of a relatively large number of in-silico methods that predict the disorder using the protein sequence as their input. We perform a first-of-its kind comprehensive empirical evaluation of the disorder predictors which is characterized by three novel aspects, (1) we evaluate the quality of the disorder predictions at the residue, segment, and chain levels; (2) we consider a large number of published and accessible to the end user predictors that are evaluated on a relatively big dataset with close to 500 proteins; and (3) we assess statistical significance of differences between the considered methods. Our study reveals that there is no universally superior predictor and that the top-performing methods are complementary. We show that while recent consensus-based predictors outperform other considered methods for the residue-level predictions, some older methods perform better for the prediction of the disordered segments. Our analysis indicates that certain predictors are biased to under-predict the disorder, while some other solutions tend to over-predict the number of the disordered residues. We also evaluate the utility of the predicted residue-level disorder for prediction of proteins with long disordered segments and prediction of the chainlevel disorder content. Lastly, we provide recommendations concerning development of a new generation of consensusbased methods and specialized methods for improved prediction of the disorder content.

During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into ‘cumulus-type’, i.e., those similar to puffy (white) clouds, and ‘stratus-type’, i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energy transmission processes. In the first class, there is limited overlap between the modules, which implies higher rigidity of the individual units; there the conformational changes can be described by an ‘energy transfer’ mechanism. In the second class, the topology presents a compact structure with significant overlap between the modules; there the conformational changes can be described by ‘multi-trajectories’; that is, multiple highly populated pathways. We further propose that disordered protein regions evolved to help other protein segments reach ‘rarely visited’ but functionally-related states. We also show the role of disorder in ‘spatial games’ of amino acids; highlight the effects of intrinsically disordered proteins (IDPs) on cellular networks and list some possible studies linking protein disorder and protein structure networks

Intrinsically unfolded proteins (IUPs) do not obey the golden rule of structural biology, 3D structure = function, as they manifest their inherent functions without resorting to three-dimensional structures. Absence of a compact globular topology in these proteins strongly implies that their ligand recognition processes should involve factors other than spatially well-defined binding pockets. Heteronuclear multidimensional (HetMulD) NMR spectroscopy assisted with a stable isotope labeling technology is a powerful tool for quantitatively investigating detailed structural features in IUPs. In particular, it allows us to delineate the presence and locations of pre-structured motifs (PreSMos) on a per-residue basis. PreSMos are the transient local structural elements that presage target-bound conformations and act as specificity determinants for IUP recognition by target proteins. Here, we present a brief chronicle of HetMulD NMR studies on IUPs carried out over the past two decades along with a discussion on the functional significance of PreSMos in IUPs.

While the crucial role of intrinsically disordered proteins (IDPs) in the cell cycle is now recognized, deciphering their molecular mode of action at the structural level still remains highly challenging and requires a combination of many biophysical approaches. Among them, small angle X-ray scattering (SAXS) has been extremely successful in the last decade and has become an indispensable technique for addressing many of the fundamental questions regarding the activities of IDPs. After introducing some experimental issues specific to IDPs and in relation to the latest technical developments, this article presents the interest of the theory of polymer physics to evaluate the flexibility of fully disordered proteins. The different strategies to obtain 3-dimensional models of IDPs, free in solution and associated in a complex, are then reviewed. Indeed, recent computational advances have made it possible to readily extract maximum information from the scattering curve with a special emphasis on highly flexible systems, such as multidomain proteins and IDPs. Furthermore, integrated computational approaches now enable the generation of ensembles of conformers to translate the unique flexible characteristics of IDPs by taking into consideration the constraints of more and more various complementary experiment. In particular, a combination of SAXS with high-resolution techniques, such as x-ray crystallography and NMR, allows us to provide reliable models and to gain unique structural insights about the protein over multiple structural scales. The latest neutron scattering experiments also promise new advances in the study of the conformational changes of macromolecules involving more complex systems.

Small heat shock proteins (sHsp) form a large ubiquitous family of proteins expressed in all phyla of living organisms. The members of this family have low molecular masses (13-43 kDa) and contain a conservative α-crystallin domain. This domain (about 90 residues) consists of several β-strands forming two β-sheets packed in immunoglobulinlike manner. The α-crystallin domain plays an important role in formation of stable sHsp dimers, which are the building blocks of the large sHsp oligomers. A large N-terminal domain and a short C-terminal extension flank the α-crystallin domain. Both the N-terminal domain and the C-terminal extension are flexible, susceptible to proteolysis, prone to posttranslational modifications, and are predominantly intrinsically disordered. Differently oriented N-terminal domains interact with each other, with the core α-crystallin domain of the same or neighboring dimers and play important role in formation of large sHsp oligomers. Phosphorylation of certain sites in the N-terminal domain affects the sHsp quaternary structure, the sHsp interaction with target proteins and the sHsp chaperone-like activity. The C-terminal extension often carrying the conservative tripeptide (I/V/L)-X-(I/V/L) is capable of binding to a hydrophobic groove on the surface of the core α-crystallin domain of neighboring dimer, thus affecting the plasticity and the overall structure of sHsp oligomers. The Cterminal extension interacts with target proteins and affects their interaction with the α-crystallin domain increasing solubility of the complexes formed by sHsp and their targets. Thus, disordered N- and C-terminal sequences play important role in the structure, regulation and functioning of sHsp.

Intrinsically disordered proteins are highly abundant in all kingdoms of life, and several protein functional classes, such as transcription factors, transcriptional regulators, hub and scaffold proteins, signaling proteins, and chaperones are especially enriched in intrinsic disorder. One of the unique cellular reactions to protein damaging stress is the socalled heat shock response that results in the upregulation of heat shock proteins including molecular chaperones. This molecular protective mechanism is conserved from prokaryotes to eukaryotes and allows an organism to respond to various proteotoxic stressors, such as heat shock, oxidative stress, exposure to heavy metals, and drugs. The heat shock response- related proteins can be expressed during normal conditions (e.g., during the cell growth and development) or can be induced by various pathological conditions, such as infection, inflammation, and protein conformation diseases. The initiation of the heat shock response is manifested by the activation of the heat shock transcription factors HSF 1, part of a family of related HSF transcription factors. This review analyzes the abundance and functional roles of intrinsic disorder in various heat shock transcription factors and clearly shows that the heat shock response requires HSF flexibility to be more efficient.