Navigating the dynamic landscape of alpha-synuclein morphology: a review of the physiologically relevant tetrameric conformation

Abstract

N-acetylated α-synuclein (αSyn) has long been established as an intrinsically disordered protein associated with a dysfunctional role in Parkinson’s disease. In recent years, a physiologically relevant, higher order conformation has been identified as a helical tetramer that is tailored by buried hydrophobic interactions and is distinctively aggregation resistant. The canonical mechanism by which the tetramer assembles remains elusive. As novel biochemical approaches, computational methods, pioneering purification platforms, and powerful imaging techniques continue to develop, puzzling information that once sparked debate as to the veracity of the tetramer has now shed light upon this new counterpart in αSyn neurobiology. Nuclear magnetic resonance and computational studies on multimeric αSyn structure have revealed that the protein folding propensity is controlled by small energy barriers that enable large scale reconfiguration. Alternatively, familial mutations ablate tetramerization and reconfigure polymorphic fibrillization. In this review, we will discuss the dynamic landscape of αSyn quaternary structure with a focus on the tetrameric conformation.

Similarity of the non-amyloid-β component and C-terminal tail of monomeric and tetrameric alpha-synuclein with 14-3-3 sigma

“…Fox Foundation-funded study indicates the 2017 economic burden of PD is nearly $52 billion in the United States alone, and projects this cost to continue increasing [3] . The largest contribution to this value is medical costs, which has led researchers to consider the non-toxic tetrameric species of αSyn as a therapeutic solution [4] , [5] , [6] . The primary focus of research on PD is largely focused on the neurotoxic effects of αSyn [1] , [5] , [7] , however, preventative therapeutics will necessarily rely on understanding the normal functions of αSyn.…”

“…The point mutations identified for αSyn (Ala-30-Pro, Glu-46-Lys, His-50-Gln, Gly-51-Asp, and Ala-53-Thr) are associated with familial PD; these mutations have been shown to modulate the propensity for aggregation [2] , [5] , [19] . There is also evidence of the stable tetrameric structure in human erythrocytes and neurons [4] , [20] , [21] , and the tetramer is proposed to exist in metastable equilibrium with the unfolded monomer [6] . Thus, while evidence suggests the disordered monomer is the predominant species physiologically [22] , [23] , αSyn also transitions to physiologically relevant ordered states that arise from binding interactions [20] , [24] .…”

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

“…This is understandable because portions of apolipoprotein sequences do have some 11-residue amphipathic α-helical repeating segments and α-Syn adopts a conformation with two antiparallel α-helices upon interactions with negatively charged membrane surfaces [16]. Furthermore, in early stages of development α-Syn can form small oligomers that fractionally occupy helical secondary structures [41–43]. These dynamic oligomers gradually morph into primarily β oligomers, possibly transitioning through a 310 helical phase [41, 44].…”

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels.

“…This is understandable because portions of apolipoprotein sequences do have some 11-residue amphipathic α-helical repeating segments and α-Syn adopts a conformation with two antiparallel α-helices upon interactions with negatively charged membrane surfaces [16]. Furthermore, in early stages of development α-Syn can form small oligomers that fractionally occupy helical secondary structures [41][42][43]. These dynamic oligomers gradually morph into primarily β oligomers, possibly transitioning through a 3 10 helical phase [41,44].…”