Intrinsically Disordered Proteins

Proteins are natural polypeptides consisting of 20 major amino acid residues, content and order of which in a given amino acid sequence defines the ability of a related protein to fold into unique functional state or to stay intrinsically disordered. Amino acid sequences code for both foldable (ordered) proteins/domains and for intrinsically disordered proteins (IDPs) and IDP regions (IDPRs), but these sequence codes are dramatically different. This difference starts with a very general property of the corresponding amino acid sequences, namely, their compositions...

Many human proteins are predicted to contain intrinsically disordered regions (IDRs), yet their occurrence in enzymes is notably rare. Human pancreatic glucokinase (GCK) is one of a small, but growing number of enzymes shown to possess an IDR. In this commentary, we summarize the results of recent biophysical studies that provide evidence for a functionally significant disorder-order transition within the IDR of GCK during the enzyme's catalytic cycle. High-resolution NMR studies indicate that kinetic cooperativity in GCK results from glucose-mediated millisecond conformational dynamics within the structurally heterogeneous and partially disordered small domain of this monomeric enzyme, whereby the precise timescale of these motions is critical for the manifestation of the kinetic cooperativity effect...

Intrinsically disordered proteins (IDPs) are an emerging concept. IDPs have high flexibility in their polypeptide chains, lacking a stable 3-dimensional structure. Because of the difficulty in performing X-ray crystallography for IDPs, nuclear magnetic resonance (NMR) spectroscopy is the first choice for atomic-level investigation of their nature. Given that isotopically labeled IDP samples are necessary for NMR study, a robust and cost-effective protocol for bacterial expression and purification of IDP is also needed...

This article continues an "Unreported Intrinsic Disorder in Proteins" series, the goal of which is to expose some interesting cases of missed (or overlooked, or ignored) disorder in proteins. The need for this series is justified by the observation that despite the fact that protein intrinsic disorder is widely accepted by the scientific community, there are still numerous instances when appreciation of this phenomenon is absent. This results in the avalanche of research papers which are talking about intrinsically disordered proteins (or hybrid proteins with ordered and disordered regions) not recognizing that they are talking about such proteins...

Intrinsically disorder has evolved in many soluble proteins because it confers a unique set of functional advantages. In contrast, the functions of membrane proteins are largely understood in terms of well-defined structures. This raises the question: Why would the evolutionary pressures that select for disorder leave membrane proteins untouched. In this hypothesis piece, I argue that intrinsic disorder may exist in membrane embedded proteins, but that it will take a different form due to the different environment...

A short segment of the disordered p53 transactivation domain (p53TAD) forms an amphipathic helix when bound to the E3 ubiquitin ligase, MDM2. In the unbound p53TAD, this short segment has transient helical secondary structure. Using a method that combines broad sampling of conformational space with re-weighting, it is shown that it is possible to generate multiple, independent structural ensembles that have highly similar secondary structure distributions for both p53TAD and a P27A mutant. Fractional amounts of transient helical secondary structure were found at the MDM2 binding site that are very similar to estimates based directly on experimental observations...

In a recent article, published in Intrinsically Disordered Proteins, a valuable consensus view regarding the nomenclature for disordered proteins was presented.(1) In this work the authors present a thoughtful and systemic review of terms that have been used in the literature to describe proteins that sample a heterogeneous set of structures during their biological lifetime. We agree that the term "intrinsically disordered proteins" (IDPs) is an appropriate single descriptor to refer to this particular class of proteins, although it does not fully capture much of the nuanced complexities that are inherent to this class...

The Φ value analysis is a method to analyze the structure of metastable states in reaction pathways. Such a methodology is based on the quantitative analysis of the effect of point mutations on the kinetics and thermodynamics of the probed reaction. The Φ value analysis is routinely used in protein folding studies and is potentially an extremely powerful tool to analyze the mechanism of binding induced folding of intrinsically disordered proteins. In this review we recapitulate the key equations and experimental advices to perform the Φ value analysis in the perspective of the possible caveats arising in intrinsically disordered systems...

This review opens a new series entitled "Unreported intrinsic disorder in proteins." The goal of this series is to bring attention of researchers to an interesting phenomenon of missed (or overlooked, or ignored, or unreported) disorder. This series serves as a companion to "Digested Disorder" which provides a quarterly review of papers on intrinsically disordered proteins (IDPs) found by standard literature searches. The need for this alternative series results from the observation that there are numerous publications that describe IDPs (or hybrid proteins with ordered and disordered regions) yet fail to recognize many of the key discoveries and publications in the IDP field...

Being the most abundant protein of the eukaryotic cell, actin continues to keep its secrets for more than 60 years. Everything about this protein, its structure, functions, and folding, is mysteriously counterintuitive, and this review represents an attempt to solve some of the riddles and conundrums commonly found in the field of actin research. In fact, actin is a promiscuous binder with a wide spectrum of biological activities. It can exist in at least three structural forms, globular, fibrillar, and inactive (G-, F-, and I-actin, respectively)...

To date there is no explanation why the development of almost all types of solid tumors occurs sharing a similar scenario: (1) creation of a cancer stem cell (CSC), (2) CSC multiplication and formation of a multicellular tumor spheroid (TS), (3) vascularization of the TS and its transformation into a vascularized primary tumor, (4) metastatic spreading of CSCs, (5) formation of a metastatic TSs and its transformation into metastatic tumors, and (6) potentially endless repetition of this cycle of events. The above gaps in our knowledge are related to the biology of cancer and specifically to tumorigenesis, which covers the process from the creation of a CSC to the formation of a malignant tumor and the development of metastases...

The current literature on intrinsically disordered proteins grows fast. To keep interested readers up to speed with this literature, we continue a "Digested Disorder" project and represent a new issue of reader's digest of the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the third quarter of 2013; i...

The current literature on intrinsically disordered proteins is overwhelming. To keep interested readers up to speed with this literature, we continue a "Digested Disorder" project and represent a series of reader's digest type articles objectively representing the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder)...

With so many diverse functions such as transporter of vitamin D metabolites and fatty acids, actin scavenger and macrophage activating factor, Gc must have been one of the most conserved proteins in animal kingdom. Our objective was to investigate the evolution of Gc by analyzing its differences at protein level. Using BLAST (Basic Local Alignment Search Tool) searches, Gc amino acid sequences were analyzed for homology. Clustal W2 and Jalview were used for multiple sequence alignment analysis, phylogenetic tree by PhyML 3...

Studies of yeast and mammalian prions introduced the idea that the protein aggregates can exist in multiple stable conformations that can be propagated by seeding. These conformational states (aka strains) were shown to have distinct physical (secondary structure, stability) and biological (cytotoxicity, infectivity) properties. For mammalian prions they were also tied to differences in disease pathology and incubation time. It was later shown that this phenomenon is not limited to prion proteins, and distinct conformational states of amyloid fibrils and oligomers derived from a variety of proteins can be propagated both in vitro and in vivo...

Protein tags of various sizes and shapes catalyze progress in biosciences. Well-folded tags can serve to solubilize proteins. Small, unfolded, peptide-like tags have become invaluable tools for protein purification as well as protein-protein interaction studies. Intrinsically Disordered Proteins (IDPs), which lack unique 3D structures, received exponentially increasing attention during the last decade. Recently, large ID tags have been developed to solubilize proteins and to engineer the pharmacological properties of protein and peptide pharmaceuticals...

Intrinsic disorder is everywhere and is inevitable. The non-folding propensity is inherent for numerous natural polypeptide chains, and many functional proteins and protein regions are intrinsically disordered. Furthermore, at particular moments in their life, most notably during their synthesis and degradation, all ordered proteins are at least partially unfolded (disordered). Also, there is a widely spread phenomenon of conditional (functional or transient) disorder, where functions of many ordered proteins require local or even global unfolding of their unique structures...

How intrinsically disordered proteins and regions evade degradation by cellular machinery evolved to recognize unfolded and misfolded chains remains a vexing question. One potential means by which this can occur is the disorder is transient in nature. That is, the disorder exists just long enough for it to be bound by a partner biomolecule and fold. A review of 30 y of studies of calmodulin's activation of calcineurin suggests that the regulatory domain of this vital phosphatase is a transiently disordered region...

The mode of action of the thermogenic inducers (salicylic acid, aspirin, and 2,6-dihydroxybenzoic acid) in the appendix of the Sauromatum guttatum inflorescence is poorly understood. Using ESI-MS and light scattering analysis, we have demonstrated that NAD(P) reductase like protein (RL) is the salicylic acid receptor in the Sauromatum appendix. RL was self-assembled in water into a large unit with a hydrodynamic diameter of 800 nm. In the presence of 1 pM salicylic acid, RL exhibited discontinuous and reversible volume phase transitions...

Thymosine β4 (Tß4) is a 43 amino acid long intrinsically disordered protein (IDP), which was initially identified as an actin-binding and sequestering molecule. Later it was described to have multiple other functions, such as regulation of endothelial cell differentiation, blood vessel formation, wound repair, cardiac cell migration, and survival.(1) The various functions of Tβ4 are mediated by interactions with distinct and structurally unrelated partners, such as PINCH, ILK, and stabilin-2, besides the originally identified G-actin...