Poster Presentation 14th Australian Peptide Conference 2022

Decoding the role of sugar tags on proteins linked to neurodegeneration (#138)

Santosh Dr Rudrawar 1 2 3 , Philip Dr Ryan 1 , George Prof Mellick 1 4 , Ming-ming Dr Xu 4 , Michael Prof Kassiou 5
  1. Griffith University, Gold Coast, QLD, Australia
  2. School of Pharmacy and Medical Science, Griffith University, Gold Coast, QLD, Australia
  3. Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia
  4. Griffith Institute fro Drug Discovery, Griffith University, Nathan Campus, QLD, Australia
  5. School of Chemistry, The University of Sydney, Sydney, NSW, Australia

Post-translational modification by enzymatic glycosylation with N-acetyl-D-glucosamine (GlcNAc) onto a proteins’ hydroxylated amino acid residues Ser/Thr is reported to deliver protective effects against the pathogenic processing of proteins with intrinsically disordered regions, which includes APP, tau and α-Syn protein.1-4

Moreover, modification of tau and α-Syn with as few as one single O-GlcNAc residue inhibits its toxic self-assembly.5-6 However, it is challenging to use whole protein to investigate the role of GlcNAc on aggregation inhibition, mechanisms underlying the aggregation event and how glycosylated proteins modulate misfolding and aggregation. We currently do not know whether O-GlcNAc modified protein binds to monomer or toxic oligomers species. To overcome these challenges, we have employed a bimodal molecular template that is composed of a recognition element and a disruption element. Inspired by natural processes taking place in healthy brain tissue, the bimodal template; small glycopeptide couples the protective effects of O-GlcNAc with the selectivity of the recognition sequence. The small glycopeptide Ac-S(GlcNAc)GAVVTGVTAV-NH2), O-GlcNAc modified peptide derived from the truncated NAC segment of α-Syn sequence, inhibited pathological aggregation of wild-type α-Syn.7 The effects of various O-GlcNAc modified peptides on wild-type α-Syn aggregation are site specific, which is in agreement with prior studies using whole O-GlcNAcylated protein. This is the first evidence that a small glycopeptide modulates protein aggregation.

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  7. 7. Ryan, P. et al. Bioorg. Chem. 2020, 94, 103389.