Targeting an Intrinsically Disordered Protein by Covalent Modification.

Intrinsically disordered proteins (IDPs) play important roles in the regulation of cellular function and in disease, and thus they represent an important group of therapeutic targets. Yet, members of this "disorderome" have not yet been successfully targeted by drugs, primarily because traditional design principles cannot be applied to their highly dynamic, heterogeneous structural states. Binders developed against IDPs so far suffer from very weak binding and inability to act in a cellular context.

Interaction between the scaffold proteins CBP by IQGAP1 provides an interface between gene expression and cytoskeletal activity.

Crosstalk between cellular pathways is often mediated through scaffold proteins that function as platforms for the assembly of signaling complexes. Based on yeast two-hybrid analysis, we report here the interaction between two complex scaffold proteins, CREB-binding protein (CBP) and the Ras GTPase-activating-like protein 1 (IQGAP1). Dissection of the interaction between the two proteins reveals that the central, thus far uncharacterized, region of IQGAP1 interacts with the HAT domain and the C-terminal intrinsically disordered region of CBP (termed ID5).

An intrinsically disordered proteins community for ELIXIR.

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are now recognised as major determinants in cellular regulation. This white paper presents a roadmap for future e-infrastructure developments in the field of IDP research within the ELIXIR framework. The goal of these developments is to drive the creation of high-quality tools and resources to support the identification, analysis and functional characterisation of IDPs.

Emergent functions of proteins in non-stoichiometric supramolecular assemblies.

Proteins are the basic functional units of the cell, carrying out myriads of functions essential for life. There are countless reports in molecular cell biology addressing the functioning of proteins under physiological and pathological conditions, aiming to understand life at the atomistic-molecular level and thereby being able to develop remedies against diseases. The central theme in most of these studies is that the functional unit under study is the protein itself.

Misprediction of Structural Disorder in Halophiles.

Whereas the concept of intrinsic disorder derives from biophysical observations of the lack of structure of proteins or protein regions under native conditions, many of our respective concepts rest on proteome-scale bioinformatics predictions. It is established that most predictors work reliably on proteins commonly encountered, but it is often neglected that we know very little about their performance on proteins of microorganisms that thrive in environments of extreme temperature, pH, or salt concentration, which may cause adaptive sequence composition bias. To address this issue, we predicted structural disorder for the complete proteomes of different extremophile groups by popular prediction methods and compared them to those of the reference mesophilic group.

Affinity purification of human m-calpain through an intrinsically disordered inhibitor, calpastatin.

Calpains are calcium-activated proteases that have biomedical and biotechnological potential. Their activity is tightly regulated by their endogenous inhibitor, calpastatin that binds to the enzyme only in the presence of calcium. Conventional approaches to purify calpain comprise multiple chromatographic steps, and are labor-intensive, leading to low yields.