The N-terminal Helix Controls the Transition Between the Soluble and Amyloid States of an FF Domain

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Mar 19

PMID 23505482

Citations 7

Authors

Virginia Castillo

Fabrizio Chiti

Salvador Ventura

Affiliations

Soon will be listed here.

Abstract

Background: Protein aggregation is linked to the onset of an increasing number of human nonneuropathic (either localized or systemic) and neurodegenerative disorders. In particular, misfolding of native α-helical structures and their self-assembly into nonnative intermolecular β-sheets has been proposed to trigger amyloid fibril formation in Alzheimer's and Parkinson's diseases.

Methods: Here, we use a battery of biophysical techniques to elucidate the conformational conversion of native α-helices into amyloid fibrils using an all-α FF domain as a model system.

Results: We show that under mild denaturing conditions at low pH this FF domain self-assembles into amyloid fibrils. Theoretical and experimental dissection of the secondary structure elements in this domain indicates that the helix 1 at the N-terminus has both the highest α-helical and amyloid propensities, controlling the transition between soluble and aggregated states of the protein.

Conclusions: The data illustrates the overlap between the propensity to form native α-helices and amyloid structures in protein segments.

Significance: The results presented contribute to explain why proteins cannot avoid the presence of aggregation-prone regions and indeed use stable α-helices as a strategy to neutralize such potentially deleterious stretches.

Citing Articles

A3DyDB: exploring structural aggregation propensities in the yeast proteome.

Garcia-Pardo J, Badaczewska-Dawid A, Pintado-Grima C, Iglesias V, Kuriata A, Kmiecik S Microb Cell Fact. 2023; 22(1):186.

PMID: 37716955 PMC: 10504709. DOI: 10.1186/s12934-023-02182-3.

Cryptic amyloidogenic regions in intrinsically disordered proteins: Function and disease association.

Santos J, Pallares I, Iglesias V, Ventura S Comput Struct Biotechnol J. 2021; 19:4192-4206.

PMID: 34527192 PMC: 8349759. DOI: 10.1016/j.csbj.2021.07.019.

Computational prediction of protein aggregation: Advances in proteomics, conformation-specific algorithms and biotechnological applications.

Santos J, Pujols J, Pallares I, Iglesias V, Ventura S Comput Struct Biotechnol J. 2020; 18:1403-1413.

PMID: 32637039 PMC: 7322485. DOI: 10.1016/j.csbj.2020.05.026.

A single cysteine post-translational oxidation suffices to compromise globular proteins kinetic stability and promote amyloid formation.

Marinelli P, Navarro S, Grana-Montes R, Bano-Polo M, Fernandez M, Papaleo E Redox Biol. 2017; 14:566-575.

PMID: 29132128 PMC: 5684091. DOI: 10.1016/j.redox.2017.10.022.

Amyloid formation by human carboxypeptidase D transthyretin-like domain under physiological conditions.

Garcia-Pardo J, Grana-Montes R, Fernandez-Mendez M, Ruyra A, Roher N, Aviles F J Biol Chem. 2014; 289(49):33783-96.

PMID: 25294878 PMC: 4256313. DOI: 10.1074/jbc.M114.594804.

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