S100A6 Amyloid Fibril Formation Is Calcium-modulated and Enhances Superoxide Dismutase-1 (SOD1) Aggregation

被引:32
作者
Botelho, Hugo M. [1 ]
Leal, Sonia S. [1 ]
Cardoso, Isabel [2 ,3 ]
Yanamandra, Kiran [4 ]
Morozova-Roche, Ludmilla A. [4 ]
Fritz, Guenter [5 ]
Gomes, Claudio M. [1 ]
机构
[1] Univ Nova Lisboa, Inst Tecnol Quim & Biol, P-2781901 Oeiras, Portugal
[2] Inst Biol Mol & Celular, Mol Neurobiol Unit, P-4150180 Oporto, Portugal
[3] Inst Politecn Porto, Escola Super Tecnol Saude Porto, P-4400330 Vila Nova De Gaia, Portugal
[4] Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden
[5] Univ Freiburg, Dept Neuropathol, D-79106 Freiburg, Germany
基金
英国医学研究理事会;
关键词
HEPARAN-SULFATE PROTEOGLYCAN; CELLULAR PRION PROTEIN; P-COMPONENT; MUTANT P53; A-BETA; ALZHEIMERS-DISEASE; BINDING-PROTEIN; METAL-IONS; MICE; RECEPTOR;
D O I
10.1074/jbc.M112.396416
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
S100A6 is a small EF-hand calcium- and zinc-binding protein involved in the regulation of cell proliferation and cytoskeletal dynamics. It is overexpressed in neurodegenerative disorders and a proposed marker for Amyotrophic Lateral Sclerosis (ALS). Following recent reports of amyloid formation by S100 proteins, we investigated the aggregation properties of S100A6. Computational analysis using aggregation predictors Waltz and Zyggregator revealed increased propensity within S100A6 helices HI and HIV. Subsequent analysis of Thioflavin-T binding kinetics under acidic conditions elicited a very fast process with no lag phase and extensive formation of aggregates and stacked fibrils as observed by electron microscopy. Ca2+ exerted an inhibitory effect on the aggregation kinetics, which could be reverted upon chelation. An FT-IR investigation of the early conformational changes occurring under these conditions showed that Ca2+ promotes anti-parallel beta-sheet conformations that repress fibrillation. At pH 7, Ca2+ rendered the fibril formation kinetics slower: time-resolved imaging showed that fibril formation is highly suppressed, with aggregates forming instead. In the absence of metals an extensive network of fibrils is formed. S100A6 oligomers, but not fibrils, were found to be cytotoxic, decreasing cell viability by up to 40%. This effect was not observed when the aggregates were formed in the presence of Ca2+. Interestingly, native S1006 seeds SOD1 aggregation, shortening its nucleation process. This suggests a cross-talk between these two proteins involved in ALS. Overall, these results put forward novel roles for S100 proteins, whose metalmodulated aggregation propensity may be a key aspect in their physiology and function.
引用
收藏
页码:42233 / 42242
页数:10
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