Alternative Conformations of the x Region of Human Protein Disulphide-Isomerase Modulate Exposure of the Substrate Binding b’ Domain

Nguyen, Van Dat; Wallis, Katrine; Howard, Mark J.; Haapalainen, Antti M.; Salo, Kirsi E.H.; Saaranen, Mirva J.; Sidhu, Ateesh; Wierenga, Rik K.; Freedman, Robert B.; Ruddock, Lloyd W.; Williamson, Richard A.

doi:10.1016/j.jmb.2008.08.085

Cited by 96 publications

(127 citation statements)

References 41 publications

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“…2c). In PDIA1 a tryptophan residue of the linker connecting domains b 0 and a 0 is inserted into the substrate-binding site positioned between helices 1 and 3 of the noncatalytic b 0 domain (Nguyen et al, 2008). In the absence of noncatalytic domains with substrate-binding sites, the interactions observed in the ERp46 crystal suggest that the third catalytic domain of ERp46 may have some ability to bind substrates via the small hydrophobic pocket on the 1-3 surface or through the exposure of residue Trp349.…”

Section: Resultsmentioning

confidence: 99%

Structure of the third catalytic domain of the protein disulfide isomerase ERp46

et al. 2012

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PDB Reference: third catalytic domain of ERp46, 3uvt.Protein disulfide isomerases are responsible for catalyzing the proper oxidation and isomerization of disulfide bonds of newly synthesized proteins in the endoplasmic reticulum. Here, the crystal structure of the third catalytic domain of protein disulfide isomerase ERp46 (also known as protein disulfide isomerase A5 and TXNDC5) was determined to 2.0 Å resolution. The structure shows a typical thioredoxin-like fold, but also identifies regions of high structural variability. In particular, the loop between helix 2 and strand 3 adopts strikingly different conformations among the five chains of the asymmetric unit. Cys381 and Cys388 form a structural disulfide and its absence in one of the molecules leads to dramatic conformational changes. The tryptophan residue Trp349 of this molecule inserts into the cavity formed by helices 1 and 3 of a neighbouring molecule, potentially mimicking the interactions of ERp46 with misfolded substrates.

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Section: Resultsmentioning

confidence: 99%

Structure of the third catalytic domain of the protein disulfide isomerase ERp46

et al. 2012

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“…In the bЈ domain, PDI has a hydrophobic binding pocket that recognizes small peptides (Pirneskoski et al, 2004) and the mutation of bЈ domain inhibits peptide binding by causing a conformational change in PDI (Nguyen et al, 2008). Moreover, the interaction between the peptides and PDI is specific and can be saturated, reversed, and abolished by the denaturation of PDI (Klappa et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Redox-regulated Export of the Major Histocompatibility Complex Class I-Peptide Complexes from the Endoplasmic Reticulum

Lee

Park

Kang

et al. 2009

MBoC

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In contrast to the fairly well-characterized mechanism of assembly of MHC class I-peptide complexes, the disassembly mechanism by which peptide-loaded MHC class I molecules are released from the peptide-loading complex and exit the endoplasmic reticulum (ER) is poorly understood. Optimal peptide binding by MHC class I molecules is assumed to be sufficient for triggering exit of peptide-filled MHC class I molecules from the ER. We now show that protein disulfide isomerase (PDI) controls MHC class I disassembly by regulating dissociation of the tapasin-ERp57 disulfide conjugate. PDI acts as a peptide-dependent molecular switch; in the peptide-bound state, it binds to tapasin and ERp57 and induces dissociation of the tapasin-ERp57 conjugate. In the peptide-free state, PDI is incompetent to bind to tapasin or ERp57 and fails to dissociate the tapasin-ERp57 conjugates, resulting in ER retention of MHC class I molecules. Thus, our results indicate that even after optimal peptide loading, MHC class I disassembly does not occur by default but, rather, is a regulated process involving PDI-mediated interactions within the peptide-loading complex. INTRODUCTIONAssembly of major histocompatibility complex (MHC) class I molecules within the endoplasmic reticulum (ER) is essential for bringing antigenic peptides to CD8 ϩ T-cells, which scan and destroy the infected and transformed cells. MHC class I quality control ensures both the ER retention of suboptimally loaded MHC class I molecules and the release of those with a higher affinity to the cell surface. Therefore, the peptide-editing process for optimal peptide loading is critical for increasing the recognition by CD8 ϩ T-cells (Van Kaer, 2002;Cresswell, 2005).MHC class I assembly is a highly regulated process mediated by several ER-resident chaperones and accessory molecules (Cresswell, 2000;Williams et al., 2002a). After initial interaction with the lectin-like chaperone calnexin, MHC class I heavy chain-␤ 2 -microglobulin (␤ 2 m) heterodimers are incorporated into the peptide-loading complex (PLC), a multimolecular unit of ER proteins that promotes optimal peptide loading into MHC class I molecules (Hammerling et al., 1998;Pamer and Cresswell, 1998;Elliott and Williams, 2005). The PLC contains calreticulin, tapasin, transporters associated with antigen processing (TAP) and two thioldependent oxidoreductases, ERp57 and protein disulfide isomerase (PDI) (Garbi et al., 2005;Park et al., 2006;Santos et al., 2007).Several functions have been proposed for tapasin in facilitating optimal peptide loading and optimization of the peptide cargo (Grandea and Van Kaer, 2001;Purcell et al., 2001;Momburg and Tan, 2002). Tapasin bridges heavy chain-␤ 2 m heterodimers to TAP (Sadasivan et al., 1996) and thus provides physical proximity between MHC class I molecules and TAP. Tapasin also retains MHC class I molecules in the ER (Schoenhals et al., 1999;Barnden et al., 2000;Grandea et al., 2000), which might enhance peptide loading. In addition, tapasin optimizes the repertoire of bound pep...

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“…60) Additionally, the b domain and x region, which is a flexible linker, stabilize the structure of b'. 61,62) The c domain is a putative Ca 2+ -binding region and also reported to play a critical role in stabilization of the functional conformation of PDI under extreme conditions. 63,64) The specific order of the domains within PDI allows for the dual activity of this enzyme, as a disulfide isomerase and a disulfide oxidase, by establishing an asymmetry in …”

Section: The Domain Structure Of Pdimentioning

confidence: 99%

Biological Functions of Protein Disulfide Isomerase as a Target of Phenolic Endocrine-disrupting Chemicals

Okada

Hashimoto

Imaoka

2010

JOURNAL OF HEALTH SCIENCE

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Endocrine disrupting chemicals (EDCs) are widespread in the environment and suspected of interfering with endocrine homeostasis. Bisphenol A (BPA), 2,2-bis(4-hydroxyphenyl)propane, an EDC, has been widely used throughout the world as an industrial chemical. BPA is a developmental, neural, and reproductive toxicant that mimics estrogen and can interfere with growth and body function. In a recent study, a BPA-binding protein was isolated from P2 fractions of rat brain, and identified as protein disulfide isomerase (PDI). PDI has been studied extensively as a key enzyme involved in the formation of the correct pattern of disulfide bonds in proteins. PDI is also known to be a membrane-associated 3,3 ,5-triiodo-L-thyronine (T 3 )-binding protein. BPA inhibits the binding of T 3 to PDI and isomerase activity of PDI. PDI has four consecutive domains, a, b, b', and a', each with a thioredoxin fold. The domains a and a' have a catalytically active Cys-Gly-His-Cys motif, while b and b' have substrate-binding sites. To address the chemical structural requirements of BPA for the inhibitory effect of PDI, several BPA analogs were tested, suggesting that the phenolic structure is important for BPA to affect PDI functions. To investigate the biological effects of BPA on PDI functions, GH3 cells were used. GH3 is a rat pituitary tumor cell line and releases growth hormone (GH) via the T 3 receptor. Over-expression of PDI suppresses the T 3 -induced release of GH and when the cells were treated with BPA together with T 3 , the amount of GH released was much increased. Thus, PDI plays an important role in the hypothalamic-pituitary-thyroid axis. In this review, the possible involvement and biological significance especially in the central nervous system, of PDI as a target of phenolic environmental chemicals, are discussed.

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Alternative Conformations of the x Region of Human Protein Disulphide-Isomerase Modulate Exposure of the Substrate Binding b’ Domain

Cited by 96 publications

References 41 publications

Structure of the third catalytic domain of the protein disulfide isomerase ERp46

Structure of the third catalytic domain of the protein disulfide isomerase ERp46

Redox-regulated Export of the Major Histocompatibility Complex Class I-Peptide Complexes from the Endoplasmic Reticulum

Biological Functions of Protein Disulfide Isomerase as a Target of Phenolic Endocrine-disrupting Chemicals

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