Open AccessMolecular insights into cell toxicity of a novel familial amyloidogenic variant of β2‐microglobulin
Author(s) -
Leri Manuela,
Bemporad Francesco,
OropesaNuñez Reinier,
Canale Claudio,
Calamai Martino,
Nosi Daniele,
Ramazzotti Matteo,
Giorgetti Sofia,
Pavone Francesco S.,
Bellotti Vittorio,
Stefani Massimo,
Bucciantini Monica
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12833
Subject(s) - beta 2 microglobulin , toxicity , cell , chemistry , computational biology , biology , bioinformatics , medicine , biochemistry , immunology
The first genetic variant of β 2 ‐microglobulin (b2M) associated with a familial form of systemic amyloidosis has been recently described. The mutated protein, carrying a substitution of Asp at position 76 with an Asn (D76N b2M), exhibits a strongly enhanced amyloidogenic tendency to aggregate with respect to the wild‐type protein. In this study, we characterized the D76N b2M aggregation path and performed an unprecedented analysis of the biochemical mechanisms underlying aggregate cytotoxicity. We showed that, contrarily to what expected from other amyloid studies, early aggregates of the mutant are not the most toxic species, despite their higher surface hydrophobicity. By modulating ganglioside GM 1 content in cell membrane or synthetic lipid bilayers, we confirmed the pivotal role of this lipid as aggregate recruiter favouring their cytotoxicity. We finally observed that the aggregates bind to the cell membrane inducing an alteration of its elasticity (with possible functional unbalance and cytotoxicity) in GM 1‐enriched domains only, thus establishing a link between aggregate‐membrane contact and cell damage.