Intrinsically Disordered Proteins

In the same way that neither a messy lab bench nor a clean one is a reliable indicator of a researcher’s productivity, a protein’s function cannot be judged solely on the basis of its neatly folded and stable domains. As evidenced by recent work discussed in this Select, we are learning that intrinsically disordered regions feature in many of the cell’s most productive multitaskers, proteins whose functions are especially fluid, dynamic, and diverse

CECAM workshop on intrinsically disordered proteins

With the increasing need to integrate different areas of science in the study of intrinsically disordered proteins we arranged a meeting entitled “Intrinsically Disordered Proteins: Connecting Computation, Physics and Biology” in Zürich in September 2013. The aim of the meeting was to bring together scientists from a range of disciplines to provide a snapshot of the field, as well as to promote future interdisciplinary studies that link the fundamental physical and chemical properties of intrinsically disordered proteins with their biological function. A range of important topics were covered at the meeting including studies linking structural studies of intrinsically disordered proteins with their function, the effect of post-translational modifications, studies of folding-upon-binding, as well as presentation of a number of systems in which intrinsically disordered proteins play a central role in important biological processes. A recurring theme was how computation, including various forms of molecular simulations, can be integrated with experimental and theoretical studies to help understand the complex properties of intrinsically disordered proteins. With this Meeting Report we hope to give a brief overview of the inspiration obtained from presentations, discussions and conversations held at the workshop and point out possible future directions within the field of intrinsically disordered proteins

Calibrated Langevin dynamics simulations of intrinsically disordered proteins

We perform extensive coarse-grained (CG) Langevin dynamics simulations of intrinsically disordered proteins (IDPs), which possess fluctuating conformational statistics between that for excluded volume random walks and collapsed globules. Our CG model includes repulsive steric, attractive hydrophobic, and electrostatic interactions between residues and is calibrated to a large collection of single-molecule fluorescence resonance energy transfer data on the inter-residue separations for 36 pairs of residues in five IDPs: $\alpha$-, $\beta$-, and $\gamma$-synuclein, the microtubule-associated protein $\tau$, and prothymosin $\alpha$. We find that our CG model is able to recapitulate the average inter-residue separations regardless of the choice of the hydrophobicity scale, which shows that our calibrated model can robustly capture the conformational dynamics of IDPs. We then employ our model to study the scaling of the radius of gyration with chemical distance in 11 known IDPs. We identify a strong correlation between the distance to the dividing line between folded proteins and IDPs in the mean charge and hydrophobicity space and the scaling exponent of the radius of gyration with chemical distance along the protein.Comment: 16 pages, 10 figure

Intrinsically disordered proteins

Nativno neuređeni proteini i proteinske regije (​engl. intrinsically disordered proteins/regions, IDP/IDR) pripadaju nedavno priznatoj skupini proteina koji su biološki aktivni usprkos nedostatku jasno definirane trodimenzionalne strukture. Za razliku od globularnih proteina, IDP u nativnom stanju ne posjeduju jedinstvenu stabilnu strukturu, već fluktuirajući skup strukturnih konformacija pogodan u staničnoj signalizaciji, regulaciji, šaperonskim aktivnostima, patogenezi bolesti i drugim raznovrsnim funckijama. Cilj ovog seminara bio je opisati osnovne značajke IDP te najvažnije eksperimentalne i bioinformatičke metode istraživanja IDP. Nadalje, rad obuhvaća podjelu IDP prema mehanizmu djelovanja i staničnoj ulozi te kratki osvrt na IDP u biljkama pri normalnim i stresnim uvjetima. U zaključku, područje IDP svjedočilo je strelovitom rastu u protekla dva desetljeća te se na temelju brojnosti i rasprostranjenosti ovih proteina predviđa velik potencijal za buduća istraživanja unutar ovog područja.Intrinsically disordered proteins and protein regions (IDP/IDR) are a recently recognized group of proteins which are biologically active despite their inherent lack of a well-defined three-dimensional structure. Unlike globular proteins, IDPs lack a unique and stable 3D structure in their native state and exist as fluctuating ensembles of conformations which are well-suited for cellular signaling, regulation, chaperone activity, disease pathogenesis and other various functions. The aim of this Bachelor’s thesis is to describe the main characteristics of IDPs and the most important experimental and bioinformatic methods used in IDP research. Moreover, the thesis includes a classification of IDPs according to functional mechanism and cellular role, as well as a brief section on IDPs in plants in normal and stressful conditions. In conclusion, the IDP field has witnessed rapid growth in the past two decades and, based on the abundance and wide spread of these proteins, there is significant potential for future research within this field

Structural characterization of intrinsically disordered proteins by NMR spectroscopy.

Recent advances in NMR methodology and techniques allow the structural investigation of biomolecules of increasing size with atomic resolution. NMR spectroscopy is especially well-suited for the study of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) which are in general highly flexible and do not have a well-defined secondary or tertiary structure under functional conditions. In the last decade, the important role of IDPs in many essential cellular processes has become more evident as the lack of a stable tertiary structure of many protagonists in signal transduction, transcription regulation and cell-cycle regulation has been discovered. The growing demand for structural data of IDPs required the development and adaption of methods such as 13C-direct detected experiments, paramagnetic relaxation enhancements (PREs) or residual dipolar couplings (RDCs) for the study of 'unstructured' molecules in vitro and in-cell. The information obtained by NMR can be processed with novel computational tools to generate conformational ensembles that visualize the conformations IDPs sample under functional conditions. Here, we address NMR experiments and strategies that enable the generation of detailed structural models of IDPs

Constructing ensembles for intrinsically disordered proteins

The relatively flat energy landscapes associated with intrinsically disordered proteins makes modeling these systems especially problematic. A comprehensive model for these proteins requires one to build an ensemble consisting of a finite collection of structures, and their corresponding relative stabilities, which adequately capture the range of accessible states of the protein. In this regard, methods that use computational techniques to interpret experimental data in terms of such ensembles are an essential part of the modeling process. In this review, we critically assess the advantages and limitations of current techniques and discuss new methods for the validation of these ensembles

Intrinsically Disordered Proteins within the Genome

The hundreds of millions of DNA base pairs within eukaryotic cells are not found free but packed inside the micrometre-sized nuclei through the formation of a macromolecular structure known as chromatin. Chromatin consists of a chain of nucleosomes – nucleoprotein complexes where the DNA makes ∼1.75 turns around a protein octamer core composed of two copies each of H2A, H2B, H3 and H4 histones. A fifth histone H1 binds on the nucleosomal surface close to the entry/exit site of DNA, interacts with linker DNA and aids in chromatin compaction. Enabling the condensation of DNA to fit into the nucleus is however only one-half of chromatin’s role. The three-dimensional spatial organization of chromatin serves a second important role in allowing the capability to exert control over gene expression. The chromatin structure thus serves as an additional layer of complexity above the genome code and permits the transcription of different proteins varying with cell lineages/cycles. The proteins that makeup, modify and read the chromatin structure are particularly enriched in `Intrinsic Disorder’ – a class of proteins lacking a well-defined structure but existing as a dynamic ensemble of rapidly interchanging states. While folded proteins with well-defined structures are amenable to be characterized through standard methods of protein structure determination, the `plasticity’ of the disordered proteins challenges the use of such ensemble averaged techniques. In this thesis, Molecular Dynamics simulations are used to characterize the disordered regions of three proteins that form the core of chromatin structure: histones, linker histones (H1) and heterochromatin protein (HP1). The carboxy-terminal domain of H1 when within the nucleosome, adopts a compact but unstructured conformation that allows its positioning between the two linker DNA strands. In contrast, the amino-terminal domain of H1 undergoes a disorder-to-order transition to an amphiphilic helical conformation. The transition to the amphiphilic helix is however subtype-dependant with the degree of condensation varying with the subtypes' nucleosomal affinity. Finally, the simulations demonstrate that the affinity of HP1 subtypes for the H3 histone is caused by the synergetic effects of both the proteins' unstructured amino-terminal domain and the structured chromodomain