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Detalhes Referência

Tipo
Artigos em Revista

Tipo de Documento
Artigo Completo

Título
Calcium binding to gatekeeper residues flanking aggregation-prone segments underlies non-fibrillar amyloid traits in superoxide dismutase 1 (SOD1)

Participantes na publicação
Sílvia G Estácio (Author)
Sónia S Leal (Author)
BioISI - Biosystems & Integrative Sciences Institute
Joana S Cristovão (Author)
BioISI - Biosystems & Integrative Sciences Institute
Patrícia Faísca (Author)
Dep. Física
BioISI
Cláudio M Gomes (Author)
Dep. Química e Bioquímica
BioISI

Resumo
Calcium deregulation is a central feature among neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Calcium accumulates in the spinal and brain stem motor neurons of ALS patients triggering multiple pathophysiological processes which have been recently shown to include direct effects on the aggregation cascade of superoxide dismutase 1 (SOD1). SOD1 is a Cu/Zn enzyme whose demetallated form is implicated in ALS protein deposits, contributing to toxic gain of function phenotypes. Here we undertake a combined experimental and computational study aimed at establishing the molecular details underlying the regulatory effects of Ca(2+) over SOD1 aggregation potential. Isothermal titration calorimetry indicates entropy driven low affinity association of Ca(2+) ions to apo SOD1, at pH7.5 and 37°C. Molecular dynamics simulations denote a noticeable loss of native structure upon Ca(2+) association that is especially prominent at the zinc-binding and electrostatic loops, whose decoupling is known to expose the central SOD1 β-barrel triggering aggregation. Structural mapping of the preferential apo SOD1 Ca(2+) binding locations reveals that among the most frequent ligands for Ca(2+) are negatively-charged gatekeeper residues located in boundary positions with respect to segments highly prone to edge-to-edge aggregation. Calcium interactions thus diminish gatekeeping roles of these residues, by shielding repulsive interactions via stacking between aggregating β-sheets, partly blocking fibril formation and promoting amyloidogenic oligomers such as those found in ALS inclusions. Interestingly, many fALS mutations occur at these positions, disclosing how Ca(2+) interactions recreate effects similar to those of genetic defects, a finding with relevance to understand sporadic ALS pathomechanisms.

Data de Publicação
2015

Instituição
BioISI - Biosystems & Integrative Sciences Institute

Suporte
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS

Identificadores da Publicação
ISSN - 1570-9639

Editora
Elsevier BV

Volume
1854
Fascículo
2

Página Inicial
118
Página Final
126

Identificadores do Documento
URL - https://www.ncbi.nlm.nih.gov/pubmed/25463043
DOI - https://doi.org/10.1016/j.bbapap.2014.11.005

Identificadores de Qualidade
SCIMAGO Q1 (2018) - 1.093 - Biophysics


Exportar referência

APA
Sílvia G Estácio, Sónia S Leal, Joana S Cristovão, Patrícia Faísca, Cláudio M Gomes, (2015). Calcium binding to gatekeeper residues flanking aggregation-prone segments underlies non-fibrillar amyloid traits in superoxide dismutase 1 (SOD1). BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 1854, 118-126. ISSN 1570-9639. eISSN . https://www.ncbi.nlm.nih.gov/pubmed/25463043

IEEE
Sílvia G Estácio, Sónia S Leal, Joana S Cristovão, Patrícia Faísca, Cláudio M Gomes, "Calcium binding to gatekeeper residues flanking aggregation-prone segments underlies non-fibrillar amyloid traits in superoxide dismutase 1 (SOD1)" in BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, vol. 1854, pp. 118-126, 2015. 10.1016/j.bbapap.2014.11.005

BIBTEX
@article{16893, author = {Sílvia G Estácio and Sónia S Leal and Joana S Cristovão and Patrícia Faísca and Cláudio M Gomes}, title = {Calcium binding to gatekeeper residues flanking aggregation-prone segments underlies non-fibrillar amyloid traits in superoxide dismutase 1 (SOD1)}, journal = {BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS}, year = 2015, pages = {118-126}, volume = 1854 }