Abstract
Protein misfolding and conformational changes are common hallmarks in many neurodegenerative diseases involving formation and deposition of toxic protein aggregates. Although many players are involved in the in vivo protein aggregation, physiological factors such as labile metal ions within the cellular environment are likely to play a key role. In this review, we elucidate the role of metal binding in the aggregation process of copper-zinc superoxide dismutase (SOD1) associated to amyotrophic lateral sclerosis (ALS). SOD1 is an extremely stable Cu-Zn metalloprotein in which metal binding is crucial for folding, enzymatic activity and maintenance of the native conformation. Indeed, demetalation in SOD1 is known to induce misfolding and aggregation in physiological conditions in vitro suggesting that metal binding could play a key role in the pathological aggregation of SOD1. In addition, this study includes recent advances on the role of aberrant metal coordination in promoting SOD1 aggregation, highlighting the influence of metal ion homeostasis in pathologic aggregation processes.
Highlights
Protein misfolding, aggregation, and formation of insoluble amyloid deposits are common pathological hallmarks in many neurological disorders such as Huntington’s, Alzheimer’s, and Parkinson’s diseases and amyotrophic lateral sclerosis (ALS) [1]
Metal ions seem to play a key role in amyloid aggregation as they were shown to be directly involved in many neurodegenerative disorders like Alzheimer’s, Parkinson’s and prion diseases
Metal ion homeostasis is a hallmark in neurodegenerative conditions [12]
Summary
Aggregation, and formation of insoluble amyloid deposits are common pathological hallmarks in many neurological disorders such as Huntington’s, Alzheimer’s, and Parkinson’s diseases and amyotrophic lateral sclerosis (ALS) [1]. Many studies have shown that wild-type human SOD1, when lacking both its metal ions, forms large and stable amyloid-like proteinions, aggregates under conditions of pH[13,14,15]. The maturation of the human SOD1 consists of the following steps: N-terminal acetylation (common to most eukaryotic cytoplasmic proteins), the insertion of copper and zinc ions, acetylation (common to most eukaryotic cytoplasmic proteins), the insertion of copper and zinc ions, the formation of a disulfide bond in each subunit, and dimerization [43,44,47]. The different melting temperatures observed for the two different dimeric SOD1 suggest that the binding of a single zinc to the disulfide-reduced form produce a more stable dimer than that obtained upon disulfide bond formation. For both apo and holo-SOD1, the unfolding process originates from the loops exposed in the structure and proceeds to the β-strands placed in its core explaining why metal binding, disulfide formation and dimerization, providing structure to many loops that connect β-strands, strongly increase the thermal stability of SOD1 [41]
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