Structures of non-prion amyloids

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We have studied several non-prion amyloids that have normal functions for their respective organisms: Pmel17, a mammalian melanocyte protein that normally forms amyloid involved in melanin biosynthesis and curli, a cell-surface amyloid of E. coli that is involved in adhesion. We found that the repeat domain of human Pmel17 is able to form an amyloid structure that forms readily at the mildly acid pH typical of the melanocyte, and rapidly dissolves at neutral pH (1). The repeat domains of Pmel17 homologs from mouse and zebrafish have little conservation of sequence, but do conserve the ability to form amyloid specifically at the acid pH of the melanosome (2). We characterized the amyloid form by curli proteins and found that they are not in the in-register parallel architecture typical of the yeast prion amyloids (3). In collaboration with the Frank Shewmaker (USUHS), we also studied the FUS protein that is found aggregated in the cytoplasm of neurons of patients with amyotrophic lateral sclerosis. We found that FUS aggregates in yeast cells, producing a marked growth inhibition (4). As in ALS neurons, FUS tends to co-aggregate with TDP-43 when co-expressed in yeast (4). 1. McGlinchey RP, Shewmaker F, McPhie P, Monterroso B, Thurber KR & Wickner RB (2009) The repeat domain of the melanosome fibril protein Pmel17 forms the amyloid core promoting melanin synthesis. Proc. Natl. Acad. Sci. USA 106: 13731-6. 2. McGlinchey, R., Shewmaker, F., Hu, K. H., McPhie, P., Tycko, R., Wickner, RB (2011) Repeat domains of melanosome matrix protein Pmel17 orthologs form amyloid fibrils at the acidic melanosomal pH. J. Biol. Chem. 286: 8385-93. 3. Shewmaker F, McGlinchey R, Thurber KR, McPhie P, Dyda F, Tycko R & Wickner RB (2009) The functional curli amyloid is not based on in-register parallel beta-sheet structure. J. Biol. Chem. 284: 25065 - 25076. 4. Kryndushkin DS, Wickner RB, Shewmaker F. FUS/TLS forms cytoplasmic aggregates, inhibits cell growth and interacts with TDP-43 in a yeast model of amyotrophic lateral sclerosis. Protein Cell 2011; 2:223 - 36.