Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies

Abstract

Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer′s, Parkinson′s, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety. A common conformational variation of these IDPs is misfolding and aggregation, forming, for instance, neurotoxic amyloid plaques. In this review, we discuss some IDPs that are involved in neurodegenerative diseases (such as beta amyloid, alpha synuclein, tau, and the “IDP-like” PrP), cancer (p53, c-Myc), and diabetes (amylin), focusing on the structural changes of these IDPs that are linked to such pathologies. We also present the IDP modulation mechanisms that can be explored in new strategies for drug design. Lastly, we show some candidate drugs that can be used in the future for the treatment of diseases caused by misfolded IDPs, considering that cancer therapy has more advanced research in comparison to other diseases, while also discussing recent and future developments in this area of research. Therefore, we aim to provide support to the study of IDPs and their modulation mechanisms as promising approaches to combat such severe diseases.

Sequence-dependent correlated segments in the intrinsically disordered region of ChiZ

“…They are involved in numerous cellular functions including regulation and signaling (2,3). As such, dysregulation, misfolding, and aggregation of IDPs lead to many diseases (4,5). While lacking defined tertiary structures, IDPs can exhibit conformational preferences, such as transient secondary structures and recurrent residue-residue contacts (e.g., salt bridges and cation-p interactions) (6,7).…”

Visualising the Experimentally Uncharted Territories of Membrane Protein Structures inside Protein Data Bank

“…2. In general, the existence of the EUTs in PDB could be attributed to the technical limitations of the biophysical tools and/or difficult sample (intrinsically disordered proteins for instance) [55][56][57][58][59] during experimental data acquisition.…”

Macromolecular Interactions of Disordered Proteins

“…The review discusses important special cases of beta-amyloid, alpha-synuclein, tau etc. They also show drug candidates for later use in to treatment of diseases caused by misfolded IDPs [38]. This is the first review from the Greb-Markiewicz lab in which Kolonko and Greb-Markiewicz summarized our current knowledge on helix-loop-helix/Per-ARNT-SIM (bHLH-PAS) proteins, considering their structures and intrinsic disorder nature based on NMR and X-ray analysis.…”