Topics

Structural fuzziness of the RNA-organizing protein SERF determines a toxic gain-of-interaction.

07:00 EST 30th November 2019 | BioPortfolio

Summary of "Structural fuzziness of the RNA-organizing protein SERF determines a toxic gain-of-interaction."

The mechanisms by which protein complexes convert from functional into pathogenic are the subject of intensive research. Here, we report how functionally unfavourable protein interactions can be induced by structural fuzziness, i.e. by persisting conformational disorder in protein complexes. We show that extreme disorder in the bound state transforms the intrinsically disordered protein SERF1a from an RNA-organizing factor into a pathogenic enhancer of alpha-synuclein (aSyn) amyloid toxicity. We demonstrate that SERF1a promotes the incorporation of RNA into nucleoli and liquid-like artificial RNA-organelles by retaining an unusually high degree of conformational disorder in the RNA-bound state. However, this type of structural fuzziness also determines an undifferentiated interaction with aSyn. RNA and aSyn both bind to one identical, positively charged site of SERF1a by an analogous electrostatic binding mode, with similar binding affinities, and without any observable disorder-to-order transition. The absence of primary or secondary structure discriminants results in SERF1a being unable to select between nucleic acid and amyloidogenic protein, leading the pro-amyloid aSyn:SERF1a interaction to prevail in the cytosol under conditions of cellular stress. We suggest that fuzzy disorder in SERF1a complexes accounts for an adverse gain-of-interaction which favours toxic binding to aSyn at the expense of non-toxic RNA binding, thereby leading to a functionally distorted and pathogenic process. Thus, structural fuzziness constitutes a direct link between extreme conformational flexibility, amyloid aggregation and the malfunctioning of RNA-associated cellular processes, three signatures of neurodegenerative proteinopathies.

Affiliation

Journal Details

This article was published in the following journal.

Name: Journal of molecular biology
ISSN: 1089-8638
Pages:

Links

DeepDyve research library

PubMed Articles [17223 Associated PubMed Articles listed on BioPortfolio]

Increased Aggregation Tendency of Alpha-Synuclein in a Fully Disordered Protein Complex.

The recent discovery of biologically active fully disordered, so called random fuzzy protein-protein interactions leads to the question of how the high flexibility of these protein complexes correlate...

Spanish validation of the mindful organizing scale: A questionnaire for the assessment of collective mindfulness.

Mindful organizing (also known as collective mindfulness) is a team level construct that is said to underpin the principles of high-reliability organizations (HROs), as it has shown to lead to almost ...

PE-SERF: A sensitivity-improved experiment to measure J in crowded spectra.

Aiming at facilitating the analysis of molecular structure, the gradient-encoded selective refocusing methods (G-SERF) and a great number of its variants for measuring proton-proton coupling constants...

Molecular basis for functional diversity among microbial Nep1-like proteins.

Necrosis and ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs) are secreted by several phytopathogenic microorganisms. They trigger necrosis in various eudicot plants upon binding to plant sphin...

Trapping and Characterization of Non-Toxic Aβ42 Aggregation Intermediates.

Amyloid β (Aβ) 42 is an aggregation-prone peptide and the believed seminal etiological agent of Alzheimer's Disease (AD). Intermediates of Aβ42 aggregation, commonly referred to as diffusible oligo...

Clinical Trials [5056 Associated Clinical Trials listed on BioPortfolio]

The Purpose of This Study is to Demonstrate the Safety and Technical Feasibility of the SERF Catheter and SERF Cardiac Ablation System to Eliminate or Control Ventricular Tachycardia (VT)

The primary objective is to demonstrate safety and feasibility of the Thermedical Ablation System and Durablate needle catheter in subjects with recurrent, monomorphic ventricular tachycar...

Saline-Enhanced Radiofrequency (SERF) Catheter Ablation for the Treatment of Ventricular Tachycardia

The purpose of this study is to demonstrate the technical feasibility of the SERF Catheter and SERF Cardiac Ablation System to eliminate or control ventricular tachycardia (VT)

A Study to Evaluate High Protein Supplementation in HIV-Positive Patients With Stable Weight Loss

The purpose of this study is to determine whether a high-quality protein food supplement will help HIV-positive patients maintain, and possibly gain, muscle mass. Many HIV-positive patien...

Comparison of Two Dose Adjustment Strategies of a Human Milk Protein Fortifier in Preterm Infants

The primary objective is to compare weight gain (g/day) of infants receiving new protein fortifier (PF) according to a blood urea nitrogen (BUN)-driven fortification regimen to weight gain...

Housing Conditions: Evaluation, Advocacy and Research in Toronto Community Housing

This project will examine whether a health promotion campaign using community organizing and joint advocacy by a coalition of tenants, health providers, social service agencies and advocat...

Medical and Biotech [MESH] Definitions

Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.

A group of antibiotics that contain 6-aminopenicillanic acid with a side chain attached to the 6-amino group. The penicillin nucleus is the chief structural requirement for biological activity. The side-chain structure determines many of the antibacterial and pharmacological characteristics. (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p1065)

Discrete protein structural units that may fold independently of the rest of the protein and have their own functions.

A toxic compound, isolated from the Spanish fly or blistering beetle (Lytta (Cantharis) vesicatoria) and other insects. It is a potent and specific inhibitor of protein phosphatases 1 (PP1) and 2A (PP2A). This compound can produce severe skin inflammation, and is extremely toxic if ingested orally.

An adaptor protein subunit of MTORC2 COMPLEX. It functions as a structural component and is phosphorylated by RIBOSOMAL PROTEIN S6 KINASES, integrating signals for cell growth and proliferation, especially during embryonic development.

Quick Search


DeepDyve research library

Relevant Topics

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...

Alzheimer's Disease
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase  'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...


Searches Linking to this Article