Dynamic Cross-Talk among Remote Binding Sites: The Molecular Basis for Unusual Synergistic Allostery

Jiao, Wanting; Hutton, Richard D.; Cross, Penelope J.; Jameson, Geoffrey B.; Parker, Emily J.

doi:10.1016/j.jmb.2011.11.037

Cited by 40 publications

(90 citation statements)

References 45 publications

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“…S6-S8). a As reported by Jiao et al 21 and Trp + Tyr) can inhibit the enzyme significantly, with Trp + Phe being the most potent combination. The binary response caused by Trp + Phe is found to be augmented by the binding of Tyr and results in almost complete loss of the enzyme activity.…”

Section: Discussionmentioning

confidence: 79%

“…When lower ligand concentrations for co-crystallization were employed (100 μM Trp and Phe), site 3 is unoccupied. 21 As these concentrations for co-crystallization were similar to those required for the inhibition by Trp + Phe, site 1 and site 2 were identified as the relevant sites for the inhibitory response to the binary combinations of Trp and Phe. Moreover, mutation of site 3 did not alter the inhibition of the enzyme by Trp and Phe.…”

Section: Resultsmentioning

confidence: 95%

“…20 Studies using molecular dynamics simulations have shown that the allostery observed in MtuDAH7PS upon Trp + Phe binding is mainly entropy driven and that inhibition is achieved by the reduction in affinity of the enzyme for its substrate E4P. 21 The central role that MtuDAH7PS plays in the regulation of aromatic amino acid biosynthesis has been further highlighted by the observation that MtuDAH7PS forms a complex with M. tuberculosis chorismate mutase, the branch point enzyme for Tyr and Phe biosynthesis. 22 Formation of this complex results in the activation of the chorismate mutase and confers regulatory properties to this enzyme, with no effect on the activity of MtuDAH7PS.…”

Section: Introductionmentioning

confidence: 99%

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Three Sites and You Are Out: Ternary Synergistic Allostery Controls Aromatic Amino Acid Biosynthesis in Mycobacterium tuberculosis

Blackmore

Reichau

Jiao

et al. 2013

Journal of Molecular Biology

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Abstract3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyzes the first step in the shikimate pathway, the pathway responsible for the biosynthesis of the aromatic amino acids Trp, Phe, and Tyr. Unlike many other organisms that produce up to three isozymes, each feedback-regulated by one of the aromatic amino acid pathway end products, Mycobacterium tuberculosis expresses a single DAH7PS enzyme that can be controlled by combinations of aromatic amino acids. This study shows that the synergistic inhibition of this enzyme by a combination of Trp and Phe can be significantly augmented by the addition of Tyr. We used X-ray crystallography, mutagenesis, and isothermal titration calorimetry studies to show that DAH7PS from M. tuberculosis possesses a Tyr-selective site in addition to the Trp and Phe sites, revealing an unusual and highly sophisticated network of three synergistic allosteric sites on one enzyme. This ternary inhibitory response, by a combination of all three aromatic amino acids, allows a tunable response of the protein to changing metabolic demands.

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Section: Discussionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Three Sites and You Are Out: Ternary Synergistic Allostery Controls Aromatic Amino Acid Biosynthesis in Mycobacterium tuberculosis

Blackmore

Reichau

Jiao

et al. 2013

Journal of Molecular Biology

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“…In the last few years, there have been a number of reports describing clear roles for protein dynamics in allosteric effects, both in the transitions between states and in making substantial contributions to the thermodynamics of the allosteric effect itself (Jiao et al 2012;Kern and Zuiderweg 2003;Law et al 2014;Manley and Loria 2012;McElroy et al 2002;Palazzesi et al 2013;Popovych et al 2006;Rivalta et al 2012;Shi and Kay 2014;Stevens et al 2001). (It is of course difficult to demonstrate the existence of allosteric effects produced solely by changes in dynamics, since the failure to observe a structural change does not mean that it does not occur; Nussinov and Tsai 2014.…”

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confidence: 99%

The role of protein dynamics in allosteric effects—introduction

Roberts

2015

Biophys Rev

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“…S1). The most intricate system discovered to date is demonstrated by the DAH7PS from Mycobacterium tuberculosis, where multiple subdomains and ligand-binding sites grafted onto the (β/α) 8 barrel are associated with a complex synergistic allostery by Phe and Trp, largely mediated by changes in protein flexibility (20). The DAH7PS enzymes from Escherichia coli and Saccharomyces cerevisiae have N-terminal barrel extensions providing a single aromatic amino acid binding site (21,22).…”

mentioning

confidence: 99%

Engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain

Cross

Allison

Dobson

et al. 2013

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

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Allosteric regulation of protein function is a critical component of metabolic control. Its importance is underpinned by the diversity of mechanisms and its presence in all three domains of life. The first enzyme of the aromatic amino acid biosynthesis, 3-deoxy-Darabino-heptulosonate 7-phosphate synthase, shows remarkable variation in allosteric response and machinery, and both contemporary regulated and unregulated orthologs have been described. To examine the molecular events by which allostery can evolve, we have generated a chimeric protein by joining the catalytic domain of an unregulated 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase with the regulatory domain of a regulated enzyme. We demonstrate that this simple gene fusion event on its own is sufficient to confer functional allostery to the unregulated enzyme. The fusion protein shares structural similarities with its regulated parent protein and undergoes an analogous major conformational change in response to the binding of allosteric effector tyrosine to the regulatory domain. These findings help delineate a remarkably facile mechanism for the evolution of modular allostery by domain recruitment.ACT domain | shikimate P rotein allostery, where ligand binding is coupled to a functional change at a remote site, is critical for the control of metabolism. For enzymes of key metabolic pathways, allostery allows precise control of catalysis in response to cellular demand. Although this important phenomenon was first described many years ago, it is only more recently that the molecular details that govern this precise control of enzyme function have been explored for a diverse range of protein systems (1-3). Functional change results from changes in the protein energy landscape elicited by ligand binding (4). This change in energy landscape may lead to conformational change and/or may be more subtly expressed as a change in protein molecular dynamics (5-12).The importance of protein allostery is underpinned by the observation that it is ubiquitous. As more proteins are studied in detail, one of the striking revelations is the variety of allosteric mechanisms that are used to control protein function. These mechanisms can be broadly divided into three groups that reflect the evolutionary path taken to acquire the allosteric functionality (5). In the first group, modification of existing structural features of a protein creates an allosteric site. Second, the formation of homo-and heterooligomeric assemblies may lead to the development of allosteric sites at the interface of subunits. Third, allostery may be endowed by domain fusion to create a modular protein with a distinct domain responsible for binding of the allosteric effector. A detailed understanding of this modular allostery, in which the allosteric effector binding site is associated with a discrete protein domain, offers the potential to generate engineered proteins with tailored functionality.The ACT domain has been identified as a modular regulatory unit associated with the control of a var...

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Dynamic Cross-Talk among Remote Binding Sites: The Molecular Basis for Unusual Synergistic Allostery

Cited by 40 publications

References 45 publications

Three Sites and You Are Out: Ternary Synergistic Allostery Controls Aromatic Amino Acid Biosynthesis in Mycobacterium tuberculosis

Three Sites and You Are Out: Ternary Synergistic Allostery Controls Aromatic Amino Acid Biosynthesis in Mycobacterium tuberculosis

The role of protein dynamics in allosteric effects—introduction

Engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain

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