Sensitivity of secondary structure propensities to sequence differences between α‐ and γ‐synuclein: Implications for fibrillation

• DOI: 10.1110/ps.062465306
• Publication Date: 2006-11-07T01:30:38Z
• Authors: Joseph A. Marsh; Vinay K. Singh; Zongchao Jia; Julie D. Forman‐Kay
• Keywords: Amyloid (mycology); Intrinsically Disordered Proteins

The synucleins are a family of intrinsically disordered proteins involved in various human diseases. alpha-Synuclein has been extensively characterized due to its role Parkinson's disease where it forms intracellular aggregates, while gamma-synuclein is overexpressed majority late-stage breast cancers. Despite fairly strong sequence similarity between the amyloid-forming regions alpha- and gamma-synuclein, only weak propensity form amyloid fibrils. We hypothesize that different fibrillation tendencies may be related differences structural propensities. Here we have measured chemical shifts for compared them previously published alpha-synuclein. In order facilitate direct comparison, implemented simple new technique re-referencing found highly effective both folded proteins. addition, developed method combines into single residue-specific secondary structure (SSP) score. observe significant Most interestingly, an increased alpha-helical region critical alpha-synuclein fibrillation, suggesting stability this protect against aggregation. This comparison propensities homologs highlights sensitivity transient changes, which suggest exploited as evolutionary mechanism fast modulation protein and, hence, function.