A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior

Sílvia G Estácio; Heinrich Krobath; Diogo Vila-Viçosa; Miguel Machuqueiro; Eugene I Shakhnovich; Patrícia F N Faísca

doi:10.1371/journal.pcbi.1003606

A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior

PLoS Comput Biol. 2014 May 8;10(5):e1003606. doi: 10.1371/journal.pcbi.1003606. eCollection 2014 May.

Authors

Sílvia G Estácio¹, Heinrich Krobath¹, Diogo Vila-Viçosa², Miguel Machuqueiro², Eugene I Shakhnovich³, Patrícia F N Faísca¹

Affiliations

¹ Centro de Física da Matéria Condensada & Departamento de Física, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
² Centro de Química e Bioquímica & Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
³ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.

Abstract

A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of β2-microglobulin (ΔN6) lacking the first six N-terminal residues. Here we perform a computational study on ΔN6, which provides clues to understand the amyloidogenicity of the full-length β2-microglobulin. Contrary to the wild-type form, ΔN6 is able to efficiently nucleate fibrillogenesis in vitro at physiological pH. This behavior is enhanced by a mild acidification of the medium such as that occurring in the synovial fluid of DRA patients. Results reported in this work, based on molecular simulations, indicate that deletion of the N-terminal hexapeptide triggers the formation of an intermediate state for folding and aggregation with an unstructured strand A and a native-like core. Strand A plays a pivotal role in aggregation by acting as a sticky hook in dimer assembly. This study further predicts that the detachment of strand A from the core is maximized at pH 6.2 resulting into higher aggregation efficiency. The structural mapping of the dimerization interface suggests that Tyr10, His13, Phe30 and His84 are hot-spot residues in ΔN6 amyloidogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloidogenic Proteins / chemistry*
Amyloidogenic Proteins / ultrastructure*
Binding Sites
Computer Simulation
Dimerization
Models, Chemical*
Models, Molecular*
Multiprotein Complexes / chemistry
Multiprotein Complexes / ultrastructure
Protein Binding
Protein Conformation
Protein Folding
Protein Structure, Tertiary
beta 2-Microglobulin / chemistry*
beta 2-Microglobulin / ultrastructure*

Substances

Amyloidogenic Proteins
Multiprotein Complexes
beta 2-Microglobulin

Grants and funding

PFNF and SGE thank the Fundação para a Ciência e a Tecnologia (FCT) for financial support through grants PTDCSAU-GMG/098274/2008 (to PFNF) and Pest-OE/FIS/UI0261/2014. PFNF and HK thank the FCT for financial support through grant PTDC/FIS/113638/2009 (to PFNF). SGE thanks FCT for financial support through post-doctoral fellowship SFRH/BPD/46313/2008. DVV thanks FCT for financial support through doctoral fellowship SFRH/BD/81017/2011. MM thanks FCT for financial support through project PEst-OE/QUI/UI0612/2011. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.