Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108797 - 108797

Published: Jan. 1, 2025

The traditional model of protein structure determined by the amino acid sequence is today seriously challenged fact that approximately half human proteome made up proteins do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered (IDPs), are involved numerous physiological functions and associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), type 2 diabetes. Targeting these challenging for two reasons: i) we need to preserve their functions, ii) drug design molecular docking possible due lack reliable starting conditions. Faced this challenge, solutions proposed artificial intelligence (AI) such as AlphaFold clearly unsuitable. Instead, suggest an innovative approach consisting mimicking, short synthetic peptides, conformational flexibility IDPs. which call adaptive derived from domains IDPs become structured after interacting ligand. Adaptive peptides designed aim selectively antagonizing harmful effects IDPs, without targeting them directly but through selected ligands, affecting properties. This"target target, arrow" strategy promised open new route discovery currently undruggable proteins.

Language: Английский

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Composite hydrogels assembled from food-grade biopolymers: Fabrication, properties, and applications

Advances in Colloid and Interface Science, Journal Year: 2024, Volume and Issue: 332, P. 103278 - 103278

Published: Aug. 14, 2024

Language: Английский

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Fluorescence-Based Protein Stability Monitoring—A Review

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1764 - 1764

Published: Feb. 1, 2024

Proteins are large biomolecules with a specific structure that is composed of one or more long amino acid chains. Correct protein structures directly linked to their correct function, and many environmental factors can have either positive negative effects on this structure. Thus, there clear need for methods enabling the study proteins, folding, components affecting stability. There significant number label-free In review, we provide general overview these methods, but main focus fluorescence-based low-instrument -expertise-demand techniques. Different aspects related thermal shift assays (TSAs), also called differential scanning fluorimetry (DSF) ThermoFluor, introduced compared isothermal chemical denaturation (ICD). Finally, discuss challenges comparative as well future opportunities assay development directions.

Language: Английский

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CONSTANS, a HUB for all seasons: How photoperiod pervades plant physiology regulatory circuits

The Plant Cell, Journal Year: 2024, Volume and Issue: 36(6), P. 2086 - 2102

Published: March 21, 2024

Abstract How does a plant detect the changing seasons and make important developmental decisions accordingly? do they incorporate daylength information into their routine physiological processes? Photoperiodism, or capacity to measure daylength, is crucial aspect of development that helps plants determine best time year vital decisions, such as flowering. The protein CONSTANS (CO) constitutes central regulator this sensing mechanism, not only activating florigen production in leaves but also participating many aspects which seasonality important. Recent discoveries place CO center gene network can length day confer seasonal input physiology senescence, seed size, circadian rhythms. In review, we discuss importance structure, function, evolutionary mechanisms embryophytes have developed annual physiology.

Language: Английский

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Encoding Structure in Intrinsically Disordered Protein Biomaterials

Accounts of Chemical Research, Journal Year: 2024, Volume and Issue: 57(3), P. 302 - 311

Published: Jan. 9, 2024

In nature, proteins range from those with highly ordered secondary and tertiary structures to that completely lack a well-defined three-dimensional structure, termed intrinsically disordered (IDPs). IDPs are generally characterized by one or more segments have compositional bias toward small hydrophilic amino acids proline residues promote structural disorder called regions (IDRs). The combination of IDRs the interactions between two determine phase behavior, function IDPs. Nature also diversifies structure thereby their functions hybridization other moieties such as glycans lipids; for instance, post-translationally glycosylated lipidated important cell membrane components. Additionally, diversity in protein is achieved nature through cross-linking within themselves domains create various topologies. For example, an essential characteristic extracellular matrix (ECM) its network components, including collagen elastin, well polysaccharides hyaluronic acid (HA). Inspired synthetic IDP (SynIDP)-based biomaterials can be designed employing similar strategies goal introducing hence unique physiochemical properties. This Account describes materials produced over past decade following approaches: (1) incorporating into SynIDPs, (2) conjugating SynIDPs either genetically encoded post-translational modification chemical conjugation, (3) engineering topology via modification. These approaches introduce modifications primary which then translated structures. Beginning point origin, may introduced each these three individually along orthogonal axes combinations three, enabling bioinspired designs theoretically span entire possibilities. Furthermore, resultant wide length scales, nano- meso- micro- even macrostructures. this Account, emphasis placed on properties features described materials. Conjugates polymers simple mixing components outside scope Account. Related biomedical applications briefly. Finally, we note future directions design functional SynIDP-based biomaterials.

Language: Английский

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The roles of intrinsically disordered proteins in neurodegeneration

Biochimica et Biophysica Acta (BBA) - General Subjects, Journal Year: 2025, Volume and Issue: unknown, P. 130772 - 130772

Published: Feb. 1, 2025

Language: Английский

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Amyloids, amorphous aggregates and assemblies of peptides – Assessing aggregation

Biophysical Chemistry, Journal Year: 2024, Volume and Issue: 308, P. 107202 - 107202

Published: Feb. 15, 2024

Language: Английский

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Illuminating the functional landscape of the dark proteome across the Animal Tree of Life through natural language processing models

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 29, 2024

Abstract Background Understanding how coding genes and their functions evolve over time is a key aspect of evolutionary biology. Protein poorly understood or characterized at the functional level may be related to important innovations, potentially leading incomplete inaccurate models change, limiting ability identify conserved lineage-specific features. Homology-based methodologies often fail transfer annotations in large fraction gene repertoire non-model organisms. This particularly relevant animals, where number yield no annotation. Results Here, we leverage homology, deep learning, protein language investigate annotation ‘dark proteome’ (defined as unknown landscape’) ca. 1,000 repertoires virtually all animal phyla, totaling 23.2 million genes. We then explored phyla revealing an enrichment immune response, viral infection, response stimuli, development, signaling, among others. Furthermore, provide open-source pipeline - FANTASIA implement benchmark these any dataset. Conclusions Our results uncover putative protein-coding across Animal Tree Life that were inaccessible before due limitations homology inference, contributing more comprehensive understanding molecular basis evolution, providing new tool for newly generated genomes.

Language: Английский

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Exploring the World of Membrane Proteins: Techniques and Methods for Understanding Structure, Function, and Dynamics

Molecules, Journal Year: 2023, Volume and Issue: 28(20), P. 7176 - 7176

Published: Oct. 19, 2023

In eukaryotic cells, membrane proteins play a crucial role. They fall into three categories: intrinsic proteins, extrinsic and that are essential to the human genome (30% of which is devoted encoding them). Hydrophobic interactions inside serve stabilize integral span lipid bilayer. This review investigates number computational experimental methods used study proteins. It encompasses variety technologies, including electrophoresis, X-ray crystallography, cryogenic electron microscopy (cryo-EM), nuclear magnetic resonance spectroscopy (NMR), biophysical methods, artificial intelligence. The link between structure function has been better understood thanks these approaches, also hold great promise for future in field. significance fusing intelligence with data improve our comprehension protein biology covered this paper. effort aims shed light on complexity by investigating methods. Overall, goal emphasize how it understand functions cells. gives general numerous look elements highlights demand multidisciplinary approaches advance understanding.

Language: Английский

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Molecular functions of ANKLE2 and its implications in human disease

Disease Models & Mechanisms, Journal Year: 2024, Volume and Issue: 17(4)

Published: April 1, 2024

ABSTRACT Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division development, the dysfunction of which increasingly implicated human disease. ANKLE2 regulates nuclear envelope disassembly at onset mitosis its reassembly after chromosome segregation. associated abnormal morphology division. It by mediating protein-protein interactions barrier to autointegration factor (BANF1; also known as BAF) kinase phosphatase that modulate phosphorylation state BAF. In brain crucial for proper asymmetric neural progenitor cells. humans, pathogenic loss-of-function mutations are primary congenital microcephaly, condition not properly developed birth. linked other disease pathologies, including Zika syndrome, cancer tauopathy. Here, we review molecular recent literature on diseases caused dysfunction.

Language: Английский

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