Investigation of intramolecular dynamics and conformations of α-, β- and γ-synuclein.
The synucleins are a family of natively unstructured proteins consisting of α-, β-, and γ-synuclein which are primarily expressed in neurons. They have been linked to a wide variety of pathologies, including neurological disorders, such as Parkinson's disease (α-synuclein) and dementia with Lewy bodies (α- and β-synuclein), as well as various types of cancers (γ-synuclein). Self-association is a key pathological feature of many of these disorders, with α-synuclein having the highest propensity to form aggregates, while β-synuclein is the least prone. Here, we used a combination of fluorescence correlation spectroscopy and single molecule Förster resonance energy transfer to compare the intrinsic dynamics of different regions of all three synuclein proteins to investigate any correlation with putative functional or dysfunctional interactions. Despite a relatively high degree of sequence homology, we find that individual regions sample a broad range of diffusion coefficients, differing by almost a factor of four. At low pH, a condition that accelerates aggregation of α-synuclein, on average smaller diffusion coefficients are measured, supporting a hypothesis that slower intrachain dynamics may be correlated with self-association. Moreover, there is a surprising inverse correlation between dynamics and bulkiness of the segments. Aside from this observation, we could not discern any clear relationship between the physico-chemical properties of the constructs and their intrinsic dynamics. This work suggests that while protein dynamics may play a role in modulating self-association or interactions with other binding partners, other factors, particularly the local cellular environment, may be more important.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.
Vanessa C
VC
Ducas
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America ; Department of Physics, Yale University, New Haven, Connecticut, United States of America.
Elizabeth
E
Rhoades
D000595:Amino Acid Sequence; D004058:Diffusion; D031541:Fluorescence Resonance Energy Transfer; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012996:Solutions; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*; D051846:beta-Synuclein / Q000737:chemistry* / Q000378:metabolism*; D051845:gamma-Synuclein / Q000737:chemistry* / Q000378:metabolism*
D012996:Solutions; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein