Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid β Peptide Client.

Filipe E P Rodrigues,Miguel Machuqueiro,Cláudio M Gomes,António J Figueira

doi:10.3390/ijms22073629

Filipe E P Rodrigues, Miguel Machuqueiro + Show 2 more

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https://doi.org/10.3390/ijms22073629

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Abstract

S100B is an astrocytic extracellular Ca2+-binding protein implicated in Alzheimer’s disease, whose role as a holdase-type chaperone delaying Aβ42 aggregation and toxicity was recently uncovered. Here, we employ computational biology approaches to dissect the structural details and dynamics of the interaction between S100B and Aβ42. Driven by previous structural data, we used the Aβ25–35 segment, which recapitulates key aspects of S100B activity, as a starting guide for the analysis. We used Haddock to establish a preferred binding mode, which was studied with the full length Aβ using long (1 μs) molecular dynamics (MD) simulations to investigate the structural dynamics and obtain representative interaction complexes. From the analysis, Aβ-Lys28 emerged as a key candidate for stabilizing interactions with the S100B binding cleft, in particular involving a triad composed of Met79, Thr82 and Glu86. Binding constant calculations concluded that coulombic interactions, presumably implicating the Lys28(Aβ)/Glu86(S100B) pair, are very relevant for the holdase-type chaperone activity. To confirm this experimentally, we examined the inhibitory effect of S100B over Aβ aggregation at high ionic strength. In agreement with the computational predictions, we observed that electrostatic perturbation of the Aβ-S100B interaction decreases anti-aggregation activity. Altogether, these findings unveil features relevant in the definition of selectivity of the S100B chaperone, with implications in Alzheimer’s disease.

Highlights

The regulation of protein aggregation by the protein quality control system is critical to main proteostasis in age-related protein deposition diseases such as Alzheimer’s disease (AD) [1]
We propose a concerted computational effort based on molecular docking and molecular dynamics simulations in order to identify and characterize the molecular details of the interaction between S100B and Aβ42
Understanding the interactions established between the S100B chaperone and its amyloid β client is critical to characterize the mechanistic aspects underlying its holdase activity and to evaluate effects on amyloid aggregation pathways

Summary

Introduction

The regulation of protein aggregation by the protein quality control system is critical to main proteostasis in age-related protein deposition diseases such as Alzheimer’s disease (AD) [1]. The concerted action of chaperone repertoires in neurons counteracts the formation of misfolded aggregates, delaying the emergence of severe proteotoxicity. Saturation of this machinery by accumulating misfolded proteins disables this protective system and neurodegeneration emerges. It has been postulated that extracellular accumulation of misfolded Ab peptides starts several years before the appearance of disease symptoms. During this prodromal stage, several responses to these early insults take place, including early neuroinflammation with the recruitment of glial cells and release of signaling mediators [2]. Recent evidence implicates this protein in multiple novel protective roles against Aβ aggregation and neurotoxic oligomer formation, including metal ion buffering scavenging [6,7] and the chaperone-like suppression of Aβ42 aggregation [8]

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