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Mechanistic study on PDI family enzymes that catalyze oxidative folding of nascent polypeptide chains

Hirayama Chihiro 東北大学

2021.04.07

概要

Over billions of years of evolution, living organisms have developed ingenious mechanisms to promote protein folding (Hartl et al., 2011). The oxidative network catalyzing protein disulfide bond formation in the endoplasmic reticulum (ER) is a prime example. While canonical protein disulfide isomerase (PDI) and ER oxidoreductin-1 (Ero1) were previously postulated to constitute a primary disulfide bond formation pathway (Araki and Inaba, 2012; Mezghrani et al., 2001; Tavender and Bulleid, 2010), more than 20 different PDI family enzymes and multiple PDI oxidases besides Ero1 have recently been identified in the mammalian ER, suggesting the development of highly diverse oxidative networks in higher eukaryotes (Nguyen et al., 2011; Schulman et al., 2010; Tavender et al., 2010). Each PDI family enzyme is likely to play a distinct role in catalyzing the oxidative folding of different substrates, concomitant with some functional redundancy, leading to the efficient production of a wide variety of secretory proteins with multiple disulfide bonds (Bulleid and Ellgaard, 2011; Okumura et al., 2015; Sato and Inaba, 2012).

Our previous in vitro studies using model substrates such as reduced and denatured bovine pancreatic trypsin inhibitor (BPTI) and ribonuclease A (RNase A) demonstrated that different PDI family enzymes participate in different stages of oxidative protein folding, resulting in the accelerated folding of native enzymes (Kojima et al., 2014; Sato et al., 2013). Multiple PDI family enzymes cooperate to synergistically increase the speed and fidelity of disulfide bond formation in substrate proteins. However, whether mechanistic insights gained by in vitro experiments using full-length substrates are applicable to real events of oxidative folding in the ER remains an important question. Indeed, some previous works demonstrated that newly synthesized polypeptide chains undergo disulfide bond formation and isomerization co-translationally, presumably via catalysis by specific PDI family members (Kadokura et al., 2020; Molinari and Helenius, 1999; Robinson and Bulleid, 2020; Robinson et al., 2020; Robinson et al., 2017). Furthermore, nascent chains play important roles in their own quality control by modulating the translation speed to increase the yield of native folding; if a nascent chain fails to fold or complete translation, then the resultant aberrant ribosome-nascent chain complexes are degraded or destabilized (Buhr et al., 2016; Chadani et al., 2017; Matsuo et al., 2017). These observations suggest that understanding real events of oxidative protein folding in cells requires systematic analysis of how PDI family enzymes act on nascent polypeptide chains during synthesis by ribosomes.

To this end, we herein developed an experimental system for directly monitoring disulfide bond formation in ribosome-associated human serum albumin (HSA) nascent chains of different lengths from the N-terminus. The resultant ribosome-nascent chain complexes (RNCs) were reacted with two ubiquitously expressed PDI family members, ER-resident protein 46 (ERp46) and canonical PDI. These two enzymes were previously shown to have distinct roles in catalyzing oxidative protein folding: ERp46 engages in rapid but promiscuous disulfide bond introduction during the early stages of folding, while PDI serves as an effective proofreader of non-native disulfides during the later stages (Kojima et al., 2014; Sato et al., 2013). The subsequent maleimidyl polyethylene glycol (mal-PEG) modification of free cysteines and Bis-Tris (pH7.0) PAGE (Nu-PAGE) analysis enabled us to detect the oxidation status of the HSA nascent chains conjugated with transfer RNA (tRNA). Using high- speed atomic force microscopy (HS-AFM), we further visualized PDI and ERp46 acting on the RNCs at the single-molecule level. Collectively, the results indicated that although both ERp46 and PDI could introduce a disulfide bond into the ribosome-associated HSA nascent chains, they demanded different lengths of the HSA segment exposed outside the ribosome exit site, and displayed different mechanisms of action against the RNC. The present systematic in vitro study using RNC containing different lengths of HSA nascent chains mimics co-translational disulfide bond formation in the ER, and the results provide a framework for understanding the mechanistic basis of oxidative nascent- chain folding catalyzed by PDI family enzymes.

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