Allosteric disulfides: Sophisticated molecular structures enabling flexible protein regulation

Chiu, Joyce; Hogg, Philip J.

doi:10.1074/jbc.rev118.005604

Cited by 106 publications

(121 citation statements)

References 109 publications

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“…The four cysteine residues are adjacent and aligned suitably for disulfide exchange reactions. Such an arrangement makes it possible for a concerted series of disulfide exchange reactions to occur (Zhou, et al, 2008) Beyond serving purely structural role, disulfide bonds can participate in redox reactions and act as allosteric switches controlling protein functions (Bekendam, et al, 2016;Butera, et al, 2018;Chiu and Hogg, 2019;Zhou, et al, 2014). Specific disulfide exchange reactions depend on a reducing agent such as thioredoxin or protein disulfide isomerase (PDI) (Zhou, et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Structural basis of SARS-CoV-2 spike protein induced by ACE2

Meirson¹,

Bomze

Markel

2020

Preprint

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MotivationThe recent emergence of the novel SARS-coronavirus 2 (SARS-CoV-2) and its international spread pose a global health emergency. The viral spike (S) glycoprotein binds the receptor (angiotensin-converting enzyme 2) ACE2 and promotes SARS-CoV-2 entry into host cells. The trimeric S protein binds the receptor using the distal receptorbinding domain (RBD) causing conformational changes in S protein that allow priming by host cell proteases. Unravelling the dynamic structural features used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal novel therapeutic targets.Using structures determined by X-ray crystallography and cryo-EM, we performed structural analysis and atomic comparisons of the different conformational states adopted by the SARS-CoV-2-RBD. ResultsHere, we determined the key structural components induced by the receptor and characterized their intramolecular interactions. We show that κ-helix (also known as polyproline II) is a predominant structure in the binding interface and in facilitating the conversion to the active form of the S protein. We demonstrate a series of conversions between switch-like κ-helix and β-strand, and conformational variations in a set of short α-helices which affect the proximal hinge region. This conformational changes lead to an alternating pattern in conserved disulfide bond configurations positioned at the hinge, indicating a possible disulfide exchange, an important allosteric switch implicated in viral entry of various viruses, including HIV and murine coronavirus. The structural information presented herein enables us to inspect and understand the important dynamic features of SARS-CoV-2-RBD and propose a novel potential therapeutic strategy to block viral entry. Overall, this study provides guidance for the design and optimization of structurebased intervention strategies that target SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

Structural basis of SARS-CoV-2 spike protein induced by ACE2

Meirson¹,

Bomze

Markel

2020

Preprint

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“…These disulfide bonds are identified by secondary structural motifs, surface exposure, and three configurations (−RHStaple, −LHHook or ±RHHook) 2 . A recent review from Chui and Hogg discusses the unique features of allosteric disulfide bonds 43 . Extracellular PDI and other oxidoreductases are major modifiers of disulfide bonds.…”

Section: Cell Surface Molecules Targeted By Extracellular Pdimentioning

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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“…A combination of mutational and immunoanalyses showed that the disulfides of the catalytic domain are formed and remain intact in the cytosol (35). Cytosolic proteins with disulfides are not common, but an analysis of disulfide bonds in the Protein Data Bank shows that 298 cytosolic or nuclear proteins contain 509 structurally defined disulfide bonds (45). Indeed, many cytosolic proteins, such as chaperones, glycolytic enzymes, and kinases, are found to contain disulfides (46).…”

Section: Cytosolic Cd38 Is Enzymatically Activementioning

confidence: 99%

“…Specific binding of cytosolic chaperones can further help the disulfide formation. This may well be the general process that allows not only type III CD38 but also the hundreds of cytosolic proteins to form and retain disulfide bonds (45,46).…”

Section: Regulation Of Type III Cd38mentioning

confidence: 99%

Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP

Lee

Zhao

2019

Journal of Biological Chemistry

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Edited by Mike Shipston Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two structurally distinct messengers that mobilize the endoplasmic and endolysosomal Ca 2؉ stores, respectively. Both are synthesized by the CD38 molecule (CD38), which has long been thought to be a type II membrane protein whose catalytic domain, intriguingly, faces to the outside of the cell. Accordingly, for more than 20 years, it has remained unresolved how CD38 can use cytosolic substrates such as NAD and NADP to produce messengers that target intracellular Ca 2؉ stores. The discovery of type III CD38, whose catalytic domain faces the cytosol, has now begun to clarify this topological conundrum. This article reviews the ideas and clues leading to the discovery of the type III CD38; highlights an innovative approach for uncovering its natural existence; and discusses the regulators of its activity, folding, and degradation. We also review the compartmentalization of cADPR and NAADP biogenesis. We further discuss the possible mechanisms that promote type III CD38 expression and appraise a proposal of a Ca 2؉-signaling mechanism based on substrate limitation and product translocation. The surprising finding of another enzyme that produces cADPR and NAADP, sterile ␣ and TIR motif-containing 1 (SARM1), is described. SARM1 regulates axonal degeneration and has no sequence similarity with CD38 but can catalyze the same set of multireactions and has the same cytosolic orientation as the type III CD38. The intriguing finding that SARM1 is activated by nicotinamide mononucleotide to produce cADPR and NAADP suggests that it may function as a regulated Ca 2؉-signaling enzyme like CD38.

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Allosteric disulfides: Sophisticated molecular structures enabling flexible protein regulation

Cited by 106 publications

References 109 publications

Structural basis of SARS-CoV-2 spike protein induced by ACE2

Structural basis of SARS-CoV-2 spike protein induced by ACE2

Protein disulfide isomerase in cardiovascular disease

Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP

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