The Protein Disulfide Isomerase Family: from proteostasis to pathogenesis

Matsusaki, Motonori; Kanemura, Shingo; Kinoshita, Misaki; Lee, Young Ho; Inaba, Kenji; Okumura, Masaki

doi:10.1016/j.bbagen.2019.04.003

Cited by 73 publications

(80 citation statements)

References 158 publications

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“…In addition, endoplasmic reticulum (ER) enzymes such as PDI can break and reorganize disulfide bonding, until the final thermodynamically driven disulfide bonding configuration is achieved ( Braakman and Hebert, 2013 ; Wallis and Freedman, 2013 ). ER transit time influences the ability of PDI to carry out disulfide reorganization of client proteins ( Matsusaki et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands

et al. 2020

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Summary Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated the reverse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally occurring TrkC receptor isoforms (TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owing to their differential association with Protein Disulfide Isomerase the isoforms have different disulfide bonding and conformations at the ectodomain. Conformations were exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligands NT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways, whereas PTP-sigma activates biased signals. Our data support an “in-to-out” model controlling receptor ectodomain conformation, a strategy that enables heterogeneity in receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.

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Section: Resultsmentioning

confidence: 99%

Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands

et al. 2020

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“…Arguably, the most recognized enzymatic source of ER peroxide is the flavoprotein ERO1. Together with members of the PDI family of oxidoreductases [ 41 ], ERO1 facilitates the formation of disulfide bonds in folding nascent polypeptides [ 42 ]. Electrons removed during the formation of a disulfide bond are transferred from the nascent secretory protein to ERO1 via PDI.…”

Section: Sources Of Er-localized H 2 Omentioning

confidence: 99%

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

Roscoe

Sevier

2020

Cells

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The endoplasmic reticulum (ER) has emerged as a source of hydrogen peroxide (H2O2) and a hub for peroxide-based signaling events. Here we outline cellular sources of ER-localized peroxide, including sources within and near the ER. Focusing on three ER-localized proteins—the molecular chaperone BiP, the transmembrane stress-sensor IRE1, and the calcium pump SERCA2—we discuss how post-translational modification of protein cysteines by H2O2 can alter ER activities. We review how changed activities for these three proteins upon oxidation can modulate signaling events, and also how cysteine oxidation can serve to limit the cellular damage that is most often associated with elevated peroxide levels.

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“…Studies using tissue-specific PDI conditional KO (CKO) mice have demonstrated that intravascular cell-derived PDI contributes to the pathology of thrombosis, inflammation, and thromboinflammation 11,12,16 . Since PDI family member thiol isomerases have recently been reviewed elsewhere 17,18 , this review will focus on the pathophysiological role of PDI in cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

Protein disulfide isomerase in cardiovascular disease

et al. 2020

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Protein disulfide isomerase (PDI) participates in the pathogenesis of numerous diseases. Increasing evidence indicates that intravascular cell-derived PDI plays an important role in the initiation and progression of cardiovascular diseases, including thrombosis and vascular inflammation. Recent studies with PDI conditional knockout mice have advanced our understanding of the function of cell-specific PDI in disease processes. Furthermore, the identification and development of novel small-molecule PDI inhibitors has led into a new era of PDI research that transitioned from the bench to bedside. In this review, we will discuss recent findings on the regulatory role of PDI in cardiovascular disease.

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The Protein Disulfide Isomerase Family: from proteostasis to pathogenesis

Cited by 73 publications

References 158 publications

Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands

Alternative Splicing of a Receptor Intracellular Domain Yields Different Ectodomain Conformations, Enabling Isoform-Selective Functional Ligands

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

Protein disulfide isomerase in cardiovascular disease

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