Abstract
α-Synuclein is the aggregation-prone protein associated with Parkinson’s disease (PD) and related neurodegenerative diseases. Complicating both its biological functions and toxic aggregation are a variety of posttranslational modifications. These modifications have the potential to either positively or negatively affect α-synuclein aggregation, raising the possibility that the enzymes that add or remove these modifications could be therapeutic targets in PD. Synthetic protein chemistry is uniquely positioned to generate site-specifically and homogeneously modified proteins for biochemical study. Here, we review the application of synthetic peptides and proteins towards understanding the effects of α-synuclein posttranslational modifications.
Highlights
As biomedical advances lead to extensions in average life-expectancy, understanding age-related neurodegenerative diseases becomes increasingly important, in the industrialized world.Alzheimer’s disease alone was the sixth leading cause of death in the United States in 2008 [1].treatments for these diseases are only palliative and effective diagnostic, preventative, Biomolecules 2015, 5 and curative therapeutic options are needed [2]
We explored the degradation of mono-ubiquitinated -synuclein using the disulfide-directed ubiquitination approach (Figure 3b) [90]
We demonstrated that this glycopeptide did not accelerate the aggregation of -synuclein, while unmodified peptides from the non-amyloid beta component (NAC) region did [106], indicating that O-GlcNAcylation at T72 will likely inhibit the aggregation of full-length protein
Summary
As biomedical advances lead to extensions in average life-expectancy, understanding age-related neurodegenerative diseases becomes increasingly important, in the industrialized world. The N-terminal region (residues 1–60) contains lysine-rich, repetitive segments that are critical for interactions with membranes This is followed by non-amyloid beta component (NAC), compromising amino acids 61–95, which is made up of predominantly hydrophobic residues and is required for -synuclein aggregation. Enables the selective reaction of protein or peptide thioesters with N-terminal cysteine residues, allowing for the generation of native peptides bonds under physiological conditions and without any protecting groups. Proteins recombinantly expressed as N-terminal fusions to one of these inteins can be cleaved by the addition of exogenous thiols to generate protein thioesters that can partake in NCL reactions in a process termed expressed protein ligation (EPL, Figure 2b) [45,46,47,48], which enables the systematic incorporation of synthetic peptides into large proteins
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