The flexibility and dynamics of protein disulfide isomerase

Römer, Rudolf A.; Wells, Stephen A.; Jimenez‐Roldan, J. Emilio; Bhattacharyya, Moitrayee; Vishweshwara, Saraswathi; Freedman, Robert B.

doi:10.1002/prot.25159

Cited by 26 publications

(47 citation statements)

References 52 publications

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“…We focus on the lowest frequency nontrivial modes of motion, which represent large‐scale motions that are likely to be on relatively long (ms) timescales. Recent studies have shown excellent agreement between flexible motion simulations and large‐scale functional motion in enzymes, with results from the calculations found to be consistent with those produced by molecular dynamic simulations . Example results are shown in Fig.…”

Section: Resultsmentioning

confidence: 65%

A complete thermodynamic analysis of enzyme turnover links the free energy landscape to enzyme catalysis

et al. 2017

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Our understanding of how enzymes work is coloured by static structure depictions where the enzyme scaffold is presented as either immobile, or in equilibrium between well-defined static conformations. Proteins, however, exhibit a large degree of motion over a broad range of timescales and magnitudes and this is defined thermodynamically by the enzyme free energy landscape (FEL). The role and importance of enzyme motion is extremely contentious. Much of the challenge is in the experimental detection of so called 'conformational sampling' involved in enzyme turnover. Herein we apply combined pressure and temperature kinetics studies to elucidate the full suite of thermodynamic parameters defining an enzyme FEL as it relates to enzyme turnover. We find that the key thermodynamic parameters governing vibrational modes related to enzyme turnover are the isobaric expansivity term and the change in heat capacity for enzyme catalysis. Variation in the enzyme FEL affects these terms. Our analysis is supported by a range of biophysical and computational approaches that specifically capture information on protein vibrational modes and the FEL (all atom flexibility calculations, red edge excitation shift spectroscopy and viscosity studies) that provide independent evidence for our findings. Our data suggest that restricting the enzyme FEL may be a powerful strategy when attempting to rationally engineer enzymes, particularly to alter thermal activity. Moreover, we demonstrate how rational predictions can be made with a rapid computational approach.

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Section: Resultsmentioning

confidence: 65%

A complete thermodynamic analysis of enzyme turnover links the free energy landscape to enzyme catalysis

et al. 2017

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“…We have applied this method to explore the flexibility of yPDI [74] and hPDI [75] , and summarise the results here; full descriptions of the simulated trajectories, expressed as a series of PDB data files, plus other analyses can be found on the associated web-site [75] . The analyses were based on the original high resolution yPDI structure 2B5E [12] , and the oxidized ( 4EL1 ) and reduced ( 4EKZ ) hPDI structures [14] .…”

Section: Modelling the Flexibility Of Pdimentioning

confidence: 99%

‘Something in the way she moves’: The functional significance of flexibility in the multiple roles of protein disulfide isomerase (PDI)

Freedman

Desmond

Byrne

et al. 2017

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Protein disulfide isomerase (PDI) has diverse functions in the endoplasmic reticulum as catalyst of redox transfer, disulfide isomerization and oxidative protein folding, as molecular chaperone and in multi-subunit complexes. It interacts with an extraordinarily wide range of substrate and partner proteins, but there is only limited structural information on these interactions. Extensive evidence on the flexibility of PDI in solution is not matched by any detailed picture of the scope of its motion. A new rapid method for simulating the motion of large proteins provides detailed molecular trajectories for PDI demonstrating extensive changes in the relative orientation of its four domains, great variation in the distances between key sites and internal motion within the core ligand-binding domain. The review shows that these simulations are consistent with experimental evidence and provide insight into the functional capabilities conferred by the extensive flexible motion of PDI.

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“…PDI is a highly flexible molecule that exhibits a particularly high degree of flexibility in the b'-x-a' region. In its reduced form, PDI can assume a very compact structure, enabling interaction of the N-terminal and C-terminal active site motifs [13,14]. In contrast, oxidized PDI demonstrates a more extended confirmation, as evidenced by high resolution evaluation of crystal structure [15] and small angle x-ray scattering [16].…”

Section: Pdi Structure-functionmentioning

confidence: 99%

Advances in vascular thiol isomerase function

Flaumenhaft

2017

Current Opinion in Hematology

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PURPOSE OF REVIEW This review will provide an overview of several recent advances in the field of vascular thiol isomerase function. RECENT FINDINGS The initial observation that protein disulfide isomerase (PDI) functions in thrombus formation occurred approximately a decade ago. At the time, there was little understanding regarding how PDI or other vascular thiol isomerases contribute to thrombosis. While this problem is far from solved, the past few years have seen substantial progress in several areas that will be reviewed in this article. (1) The relationship between PDI structure and its function has been investigated and applied to identify domains of PDI that are critical for thrombus formation. (2) The mechanisms that direct thiol isomerase storage and release from platelets and endothelium have been studied. (3) New techniques including kinetic-based trapping have identified substrates that vascular thiol isomerases modify during thrombus formation. (4) Novel inhibitors of thiol isomerases have been developed that are useful both as tools to interrogate PDI function and as potential therapeutics. (5) Human studies have been conducted to measure circulating PDI in disease states and evaluate the effect of oral administration of a PDI inhibitor on ex vivo thrombin generation. SUMMARY Current findings indicate that thiol isomerase-mediated disulfide bond modification in receptors and plasma proteins is an important layer of control of thrombosis and vascular function more generally.

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The flexibility and dynamics of protein disulfide isomerase

Cited by 26 publications

References 52 publications

A complete thermodynamic analysis of enzyme turnover links the free energy landscape to enzyme catalysis

A complete thermodynamic analysis of enzyme turnover links the free energy landscape to enzyme catalysis

‘Something in the way she moves’: The functional significance of flexibility in the multiple roles of protein disulfide isomerase (PDI)

Advances in vascular thiol isomerase function

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