Structures of Human Peroxiredoxin 3 Suggest Self-Chaperoning Assembly that Maintains Catalytic State

We propose a new role for the high molecular weight form as a selfchaperoning assembly maintaining HsPrx3 function under stress

N. Amy Yewdall; Hariprasad Venugopal; Ambroise Desfosses; Vahid Abrishami; Yuliana Yosaatmadja; Mark B. Hampton; Juliet A. Gerrard; David C. Goldstone; Alok K. Mitra; Mazdak Radjainia

2016

Scholarcy highlights

  • Mitochondria are a major intracellular source of superoxide and hydrogen peroxide
  • Human peroxiredoxin 3 is localized to the mitochondria and, because of its high abundance and reactivity with H2O2, the reduced protein is the preferred target for 90% of mitochondrial H2O2
  • The active-site pocket is located in an area of strong positive charge consistent with a binding site for H2O2, while the surface surrounding the active site is hydrophobic in nature
  • When all the symmetry equivalent molecules in the crystal lattice were generated, an organization α7 C-terminal tail was revealed comprising three stacked dodecameric rings forming a short helical filament formally analogous to the helical high molecular weight filaments of HsPrx3 produced at low pH and studied by us earlier at $7-Aresolution
  • Inspection of the active site in the current 4.1-Amodel derived from the cryoelectron microscopy map of the HsPrx3 HMW form confirms our earlier result that this region is locally unfolded, as observed in the double stack of SmPrx1 crystal structure
  • Of HsPrx3 dodecameric toroids that were geometrically very similar to the bona fide low-pH, helical assemblies. Both the Xray crystal structure and cryo-EM results demonstrate that HsPrx3 is able to organize into HMW assemblies at pH 8.5, wherein the active site is in the fully folded state, as well as at acidic pH, wherein instead the active site is in the LU state
  • We propose a new role for the high molecular weight form as a selfchaperoning assembly maintaining HsPrx3 function under stress

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