Defining the mechanism of PDI interaction with disulfide-free amyloidogenic proteins: Implications for exogenous protein expression and neurodegenerative disease

Pingyu Yan, Zhiyuan Zou, Shiyao Zhang, Rui Wang, Tingting Niu, Xia Zhang, Defu Liu, Xuejie Zhou, Alan K. Chang, Nathaniel G.N. Milton, Gary W. Jones, Jianwei He

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Protein disulfide isomerase (PDI) is an important molecular chaperone capable of facilitating protein folding in addition to catalyzing the formation of a disulfide bond. 

To better understand the distinct substrate-screening principles of Pichia pastoris PDI (Protein disulfide isomerase) and the protective role of PDI in amyloidogenic diseases, we investigated the expression abundance and intracellular retention levels of three archetypal amyloidogenic disulfide bond-free proteins (Aβ42, α-synuclein (α-Syn) and SAA1) in P. pastoris GS115 strain without and with the overexpression of PpPDI (P. pastoris PDI).

Intriguingly, amyloidogenic Aβ42 and α-Syn were detected only as intracellular proteins whereas amyloidogenic SAA1 was detected both as intracellular and extracellular proteins when these proteins were expressed in the PpPDI-overexpressing GS115 strain. 

The binding between PpPDI and each of the three amyloidogenic proteins was investigated by molecular docking and simulations. 

Three different patterns of PpPDI-substrate complexes were observed, suggesting that multiple modes of binding might exist for the binding between PpPDI and its amyloidogenic protein substrates, and this could represent different specificities and affinities of PpPDI toward its substrates. Further analysis of the proteomics data and functional annotations indicated that PpPDI could eliminate the need for misfolded proteins to be partitioned in ER-associated compartments.

Original languageEnglish
Pages (from-to)175-184
Number of pages10
JournalInternational Journal of Biological Macromolecules
Volume174
DOIs
Publication statusPublished - 31 Mar 2021
Externally publishedYes

Keywords

  • Amyloidogenic protein
  • Molecular chaperone
  • Protein disulfide isomerase

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