title: A Raman optical activity study of rheomorphism in caseins, synucleins and tau. New insight into the structure and behaviour of natively unfolded proteins.
abstract: The casein milk proteins and the brain proteins alpha-synuclein and tau have been described as natively unfolded with random coil structures, which, in the case of alpha-synuclein and tau, have a propensity to form the fibrils found in a number of neurodegenerative diseases. New insight into the structures of these proteins has been provided by a Raman optical activity study, supplemented with differential scanning calorimetry, of bovine beta- and kappa-casein, recombinant human alpha-, beta- and gamma-synuclein, together with the A30P and A53T mutants of alpha-synuclein associated with familial cases of Parkinson's disease, and recombinant human tau 46 together with the tau 46 P301L mutant associated with inherited frontotemporal dementia. The Raman optical activity spectra of all these proteins are very similar, being dominated by a strong positive band centred at approximately 1318 cm(-1) that may be due to the poly(l-proline) II (PPII) helical conformation. There are no Raman optical activity bands characteristic of extended secondary structure, although some unassociated beta strand may be present. Differential scanning calorimetry revealed no thermal transitions for these proteins in the range 15-110 degrees C, suggesting that the structures are loose and noncooperative. As it is extended, flexible, lacks intrachain hydrogen bonds and is hydrated in aqueous solution, PPII helix may impart a rheomorphic (flowing shape) character to the structure of these proteins that could be essential for their native function but which may, in the case of alpha-synuclein and tau, result in a propensity for pathological fibril formation due to particular residue properties.
authors.affiliation: Department of Chemistry, University of Glasgow, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Syme
authors.forename: Ewan W
authors.initials: EW
authors.lastname: Blanch
authors.forename: Carl
authors.initials: C
authors.lastname: Holt
authors.forename: Ross
authors.initials: R
authors.lastname: Jakes
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.forename: Lutz
authors.initials: L
authors.lastname: Hecht
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Barron
mesh_terms: D000818:Animals; D002364:Caseins / Q000737:chemistry*; D002417:Cattle; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013059:Spectrum Analysis, Raman; D051843:Synucleins; D051844:alpha-Synuclein; D051845:gamma-Synuclein; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D002364:Caseins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051845:gamma-Synuclein; D016875:tau Proteins