Editorial [Hot topic: Structural Disorder in Viral Proteins (Guest Editor: Sonia Longhi)]
Abstract:The notion that protein function relies on a precise 3D structure constitutes one of the central paradigms of biochemistry. According to this concept, a protein can perform its biological function(s) only after folding into a unique 3D structure, and all the information necessary for a protein to fold into this unique 3D structure (in a given environment) is encoded in the amino acid sequence. Only recently has the validity of this structure-function paradigm been seriously challenged, primarily through the wealth of counterexamples that have gradually accumulated over the past 20-25 years. These counterexamples demonstrated that many functional proteins or protein parts exist in an entirely or partly disordered state. Intrinsically disordered proteins (IDPs), also referred to as natively unfolded proteins, lack a unique, stable 3D structure in solution, existing instead as a dynamic ensemble of conformations and exerting their biological activity without a prerequisite stably folded structure.
IDPs possess a distinct combination of a high content of charged residues and of a low content of hydrophobic residues that allows them to be distinguished from globular proteins. These peculiar sequence features have led to the development of various disorder predictors, which allowed an estimation of the occurrence of disorder in biological systems. These studies showed that the frequency and length of disordered regions increases with increasing organism's complexity. For example, long intrinsically disordered regions have been predicted to occur in 33% of eukaryotic proteins, with 12% of these latter being fully disordered. Furthermore, viruses and eukaryota were predicted to have ten times more conserved disorder (roughly 1%) than archaea and bacteria (0.1%). Beyond these computational studies, an increasing amount of experimental evidence has been gathered in the last decade pointing out the large abundance of intrinsic disorder within the living world: more than 523 proteins containing 1195 disordered regions have been annotated so far in the Disprot data base (http://www.disprot.org).
Despite this large body of experimental evidence pointing out the abundance (and biological relevance) of disorder in the living world, the notion of a tight dependence of protein function on a precise 3D structure is still deeply anchored in many scientists' mind. The reasons for this lack of awareness or even “resistance” to the concept of protein intrinsic disorder are multiple. First, the growing numbers of protein structures determined by X-ray crystallography and by NMR in the last three decades has shifted the attention of scientists away from the numerous examples of IDPs. Second, IDPs have been long unnoticed because researchers encountering examples of structural disorder mainly ascribed them to errors and artifacts and, as such, purged them from papers and reports. Third, structural disorder is hard to conceive and classify. Fourth, IDPs have been neglected because of the perception that a limited amount of mechanistic data could be derived from their study. Yet, the evidence that IDPs exist both in vitro and in vivo is compelling and justifies considering them as a separate class within the protein realm.
Many IDPs undergo a disorder-to-order transition upon binding to their physiological partner(s), a process termed induced folding. IDPs bind to their target(s) through “molecular recognition elements” (MoREs) or “molecular recognition features” (MoRFs). MoRFs are interaction-prone short segments with an increased foldability, which are embedded within long disordered regions and which become ordered upon binding to a specific partner. The conformation of MoRFs in isolation can be either disordered or partially preformed, thus reflecting an inherent conformational preference. In this latter case, a transiently populated folded state would exist even in the absence of the partner, thus implying that the folding induced by the partner would rely (at least partly) on conformer selection (i.e. selection by the partner of a pre-existing conformation) rather than on a “fly-casting” mechanism. It has been proposed that the restriction in the conformational space of MoRFs in the unbound state could reduce the entropic cost of binding thereby enhancing affinity. IDPs can bind their target(s) with a high extent of conformational polymorphism, with binding generally involving larger normalized interface areas than those found between rigid partners, with protein interfaces being enriched in hydrophobic residues. Thus, protein-protein interactions established by IDPs rely more on hydrophobic-hydrophobic than on polar-polar contacts....
Document Type: Research Article
Publication date: August 1, 2010
More about this publication?
- Protein & Peptide Letters publishes short papers in all important aspects of protein and peptide research, including structural studies, recombinant expression, function, synthesis, enzymology, immunology, molecular modeling, drug design etc. Manuscripts must have a significant element of novelty, timeliness and urgency that merit rapid publication. Reports of crystallisation, and preliminary structure determinations of biologically important proteins are acceptable. Purely theoretical papers are also acceptable provided they provide new insight into the principles of protein/peptide structure and function.