FIGURE 11.

Model of PMEL fibril formation. The schematic diagram shows the maturation of p250 into functional amyloid fibrils. The p250 PMEL dimer is resolved to p160 via disulfide bond rearrangement with proprotein convertase cleavage occurring before, during, or after this process. p160 is then cleaved by BACE2 to Mα+Mβ′, and Mβ′ is removed to produce free Mα by an as yet unknown process. Mα then assembles into fibrils and is concomitantly or subsequently cleaved by cysteine proteases into smaller fragments including Mα′. Note that the CTF is trafficked to lysosomes and is not incorporated into functional amyloid fibrils. The fate of Mβ′ is not known. For simplicity, only one subunit of the original dimer is shown after p160. The red lines represent disulfide bonds between Cys-301 and the KLD.