Sulfenylation: an emerging element of the protein disulfide isomerase code for thrombosis

Thiol-redox processes crucially compose biological redox signaling codes. While many signaling proteins exhibit thiol-dependent modulation, code integration is provided by the so-called professional thiol-redox proteins [ [1] Oliveira P.V.S. Laurindo F.R.M. Implications of plasma thiol redox in disease. Clin Sci (Lond). 2018; 132: 1257-1280 Crossref PubMed Scopus (73) Google Scholar , [2] Tanaka L.Y. Oliveira P.V.S. Laurindo F.R.M. Peri/epicellular thiol oxidoreductases as mediators of extracellular redox signaling. Antioxid Redox Signal. 2020; 33: 280-307 Crossref PubMed Scopus (14) Google Scholar ]. For example, peroxiredoxins react rapidly with peroxides or peroxynitrite and can act as mass redox sensors and disulfide-relay proteins [ [3] Rhee S.G. Kil I.S. Multiple functions and regulation of mammalian peroxiredoxins. Annu Rev Biochem. 2017; 86: 749-775 Crossref PubMed Scopus (169) Google Scholar ]. Emerging evidence indicates that the protein disulfide isomerase (PDI) family of proteins also signals beyond their canonical role as thiol-redox protein folding catalysts in the endoplasmic reticulum (ER) [ [2] Tanaka L.Y. Oliveira P.V.S. Laurindo F.R.M. Peri/epicellular thiol oxidoreductases as mediators of extracellular redox signaling. Antioxid Redox Signal. 2020; 33: 280-307 Crossref PubMed Scopus (14) Google Scholar ]. PDIs constitute a >21-member family from the thioredoxin superfamily. The prototype PDIA1 (PDI) is a U-shaped protein displaying 4 thioredoxin-fold motifs in tandem, sequentially named a-b-b′-a′, plus a C-terminal motif carrying an ER-retrieval sequence. The a and a′ domains display redox-active Cysteine-Glycine-Histidine-Cysteine domains, while the b and b′ domains are devoid of redox-active thioredoxin motifs and enriched in hydrophobic residues for substrate binding (Figure). PDI exerts chaperone, reductase, oxidase, and isomerase activities, the latter involving reshuffling of nonnative disulfides toward native ones [ [2] Tanaka L.Y. Oliveira P.V.S. Laurindo F.R.M. Peri/epicellular thiol oxidoreductases as mediators of extracellular redox signaling. Antioxid Redox Signal. 2020; 33: 280-307 Crossref PubMed Scopus (14) Google Scholar ]. PDI-dependent signaling has been involved in a host of physiological processes and diseases, particularly in platelet aggregation and thrombosis [ [4] Gaspar R.S. Gibbins J.M. Thiol isomerases orchestrate thrombosis and hemostasis. Antioxid Redox Signal. 2021; 35: 1116-1133 Crossref PubMed Scopus (6) Google Scholar ]. Breaking the PDI signaling code is challenging but important to reveal novel mechanisms and possible therapeutic interventions.