O-GlcNAcylation of ?-Synuclein at Serine 87 Reduces Aggregation without Affecting Membrane Binding.

ABSTRACT: The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety of post-translational modifications. One such modification, O-GlcNAcylation, has been found on some of these aggregation prone proteins, including ?-synuclein, the major protein that plays a causative role in synucleinopathies like Parkinson's disease. We previously used synthetic protein chemistry to prepare ?-synuclein bearing a homogeneous O-GlcNAc modification at threonine 72 and showed that this modification inhibits protein aggregation. However, the effects of the other eight O-GlcNAcylation sites that have been identified were unknown. Here, we use a similar synthetic strategy to investigate the consequences of this modification at one of these sites, serine 87. We show that O-GlcNAcylation at this site also inhibits ?-synuclein aggregation but to a lesser extent than that for the same modification at threonine 72. However, we also find that this modification does not affect the membrane-binding properties of ?-synuclein, which differentiates it from phosphorylation at the same site. These results further support the development of therapies that can elevate O-GlcNAcylation of ?-synuclein to slow the progression of Parkinson's disease.

SUBMITTER: Lewis YE 

PROVIDER: S-EPMC5607117 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature