Allosteric sites: remote control in regulation of protein activity

Guarnera, Enrico; Berezovsky, Igor N.

doi:10.1016/j.sbi.2015.10.004

Cited by 127 publications

(136 citation statements)

References 70 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…Indeed, both k cat and K M are affected by dimerization and oxidation (Table 1). This result is consistent with the current view of allosteric inhibitory regulation of proteins (28,29) and provides a rapid means of reversible enzyme inactivation. Other combinations such as the Cys21-Cys167 and Cys21-Cys190 disulfide did not correlate with the down-regulation of AtSAL1 activity by oxidation (A).…”

Section: Atsal1 Is Redox-regulated By Dual Mechanisms Of Intramolecularsupporting

confidence: 92%

“…Allosteric regulation of protein activity is commonplace (25) and frequently involves alteration of protein dynamics and trapping of proteins in inactive conformations (26)(27)(28)(29). Thus, we performed molecular dynamics (MD) energy minimization to generate monomeric (reduced) and dimeric (oxidized) AtSAL1 models to investigate the effect of dimerization and the disulfide bonds on the protein structure and dynamics.…”

Section: Atsal1 Is Redox-regulated By Dual Mechanisms Of Intramolecularmentioning

confidence: 99%

See 1 more Smart Citation

Sensing and signaling of oxidative stress in chloroplasts by inactivation of the SAL1 phosphoadenosine phosphatase

Chan

Mabbitt

Phua

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

143

157

View full text Add to dashboard Cite

Intracellular signaling during oxidative stress is complex, with organelle-to-nucleus retrograde communication pathways ill-defined or incomplete. Here we identify the 3′-phosphoadenosine 5′-phosphate (PAP) phosphatase SAL1 as a previously unidentified and conserved oxidative stress sensor in plant chloroplasts. Arabidopsis thaliana SAL1 (AtSAL1) senses changes in photosynthetic redox poise, hydrogen peroxide, and superoxide concentrations in chloroplasts via redox regulatory mechanisms. AtSAL1 phosphatase activity is suppressed by dimerization, intramolecular disulfide formation, and glutathionylation, allowing accumulation of its substrate, PAP, a chloroplast stress retrograde signal that regulates expression of plastid redox associated nuclear genes (PRANGs). This redox regulation of SAL1 for activation of chloroplast signaling is conserved in the plant kingdom, and the plant protein has evolved enhanced redox sensitivity compared with its yeast ortholog. Our results indicate that in addition to sulfur metabolism, SAL1 orthologs have evolved secondary functions in oxidative stress sensing in the plant kingdom. There is also a shift from reducing to more oxidizing states in the redox poise of plastoquinone (PQ) and other stromal redox couples such as glutathione (GSH/GSSG). All of these changes are associated with adjustment of photosystem stoichiometry and chloroplastic metabolic enzymes by chloroplast-resident kinases (2) and redox-sensitive thioredoxins (TRXs) (3), respectively, as well as activation of signaling pathways for the induction of common and unique sets of nuclear genes (4, 5).The nuclear transcriptional response to stress in chloroplasts is mediated by chemical signals emanating from the chloroplasts to the nucleus in a process called retrograde signaling (6). There are at least seven distinct retrograde signaling pathways responding to changes in chloroplastic ROS and redox state (7), including betacyclocitral for PSII-1 O 2 responses (8) and the PAP-XRN pathway which alters expression of 25% of the HL-associated transcriptome, many of which are ROS and redox associated (9). The unique gene sets which expression are induced by PSI ROS and changes in chloroplast redox poise are collectively referred to herein as plastid redox associated nuclear genes (PRANGs) (7); they include key and common stress marker genes such as ASCORBATE PEROXIDASE 2 (APX2) (10, 11) and ZAT10 (12) critical for acclimation. The nuclear regulators of PRANGs and the subsequent chloroplasttargeted stress responses, including induction of chloroplast antioxidant and redox regulation enzymes such as redoxin proteins, have been extensively elucidated for the different retrograde pathways (7,12). Despite these advances, however, in all of the PRANG retrograde signaling pathways no chloroplastic sensor(s) of ROS and redox state has been conclusively identified (7). For instance, a previously hypothesized sensor kinase for the PQ redox state (2) has recently been reascribed to facilitate H 2 O 2 production rather than redox sensi...

show abstract

Section: Atsal1 Is Redox-regulated By Dual Mechanisms Of Intramolecularsupporting

confidence: 92%

Section: Atsal1 Is Redox-regulated By Dual Mechanisms Of Intramolecularmentioning

confidence: 99%

Sensing and signaling of oxidative stress in chloroplasts by inactivation of the SAL1 phosphoadenosine phosphatase

Chan

Mabbitt

Phua

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

143

157

View full text Add to dashboard Cite

show abstract

“…Both causality and energetics of the allosteric pathway identify the mechanisms governing the regulation of this action 22 . There are some methods that examine the causality of the perturbations within the allosteric path 23, 24 .…”

Section: Resultsmentioning

confidence: 99%

Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase

Karamzadeh

Karimi‐Jafari

Sharifi-Zarchi

et al. 2017

Sci Rep

View full text Add to dashboard Cite

The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening-closing structure variations are highlighted on projected free energy landscapes. Then, important structural features that exhibit considerable differences in dynamics of redox states are extracted by statistical machine learning methods. Mapping the structural variations to time series of residue interaction networks also provides a holistic representation of the dynamical redox differences. With emphasizing on persistent long-lasting interactions, an approach is proposed that compiled these time series networks to a single dynamic residue interaction network (DRIN). Differential comparison of DRIN in oxidized and reduced states reveals chains of residue interactions that represent potential allosteric paths between catalytic and ligand binding sites of hPDI.

show abstract

“…The potential benefits are far-reaching because while many proteins are not naturally regulated in vivo by an allosteric mechanism, it has been speculated that all proteins have potential or hidden allosteric sites and that these locations can be exploited for drug design purposes [4]. Experimental and computational methods have been proposed to identify these unknown sites in allosteric and non-allosteric proteins [5–7], and while some approaches have been successful [6,8], the need for additional methods is clear [6]. …”

Section: Introductionmentioning

confidence: 99%

Leveraging Reciprocity to Identify and Characterize Unknown Allosteric Sites in Protein Tyrosine Phosphatases

Cui

Beaumont

Ginther

et al. 2017

Journal of Molecular Biology

View full text Add to dashboard Cite

Drug-like molecules targeting allosteric sites in proteins are of great therapeutic interest; however, identification of potential sites is not trivial. A straightforward approach to identify hidden allosteric sites is demonstrated in protein tyrosine phosphatases (PTP) by creation of single alanine mutations in the catalytic acid loop of PTP1B and VHR. This approach relies on the reciprocal interactions between an allosteric site and its coupled orthosteric site. The resulting NMR chemical shift perturbations (CSPs) of each mutant reveal clusters of distal residues affected by acid loop mutation. In PTP1B and VHR, two new allosteric clusters were identified in each enzyme. Mutations in these allosteric clusters detrimentally altered phosphatase activity with reductions in kcat/KM ranging from 30% to nearly 100-fold. This work outlines a simple method for identification of new allosteric sites in PTP, and given the basis of this method in thermodynamics, it is expected to be generally useful in other systems.

show abstract

Allosteric sites: remote control in regulation of protein activity

Cited by 127 publications

References 70 publications

Sensing and signaling of oxidative stress in chloroplasts by inactivation of the SAL1 phosphoadenosine phosphatase

Sensing and signaling of oxidative stress in chloroplasts by inactivation of the SAL1 phosphoadenosine phosphatase

Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase

Leveraging Reciprocity to Identify and Characterize Unknown Allosteric Sites in Protein Tyrosine Phosphatases

Contact Info

Product

Resources

About