Biological messiness vs. biological genius: Mechanistic aspects and roles of protein promiscuity

Atkins, William M.

doi:10.1016/j.jsbmb.2014.09.010

Cited by 41 publications

(39 citation statements)

References 73 publications

(78 reference statements)

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“…Robust signaling pathways must not only respond to activating ligands but must discriminate against the wrong ones to reduce noise (50). For LRH-1, this challenge is amplified because its ligands include highly abundant intact PLs that include a large fraction of cell membranes.…”

Section: Discussionmentioning

confidence: 99%

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity

Musille

Kossmann

Kohn

et al. 2016

Journal of Biological Chemistry

104

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Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog-1 (LRH-1), which has evolved a novel allosteric pathway to support appropriate interaction with co-regulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of metabolic and neoplastic diseases. Although the prospect of modulating LRH-1 via small molecules is exciting, the molecular mechanism linking PL structure to transcriptional co-regulator preference is unknown. Previous studies showed that binding to an activating PL ligand, such as dilauroylphosphatidylcholine, favors LRH-1's interaction with transcriptional coactivators to up-regulate gene expression. Both crystallographic and solution-based structural studies showed that dilauroylphosphatidylcholine binding drives unanticipated structural fluctuations outside of the canonical activation surface in an alternate activation function (AF) region, encompassing the ␤-sheet-H6 region of the protein. However, the mechanism by which dynamics in the alternate AF influences co-regulator selectivity remains elusive. Here, we pair x-ray crystallography with molecular modeling to identify an unexpected allosteric network that traverses the protein ligand binding pocket and links these two elements to dictate selectivity. We show that communication between the alternate AF region and classical AF2 is correlated with the strength of the co-regulator interaction. This work offers the first glimpse into the conformational dynamics that drive this unusual PL-mediated nuclear hormone receptor activation.

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Section: Discussionmentioning

confidence: 99%

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity

Musille

Kossmann

Kohn

et al. 2016

Journal of Biological Chemistry

104

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“…Recent data have suggested that a large number of enzymes can catalyse more than one chemical transformation. This phenomenon, referred to as enzyme “promiscuity”, is now considered as being the rule rather than the exception (Atkins, ; Khersonsky & Tawfik, ). It is believed to have played a central role in the evolution of enzymatic functions across several protein superfamilies, because promiscuous activities can rapidly be enhanced with a limited number of mutations (Glasner, Gerlt, & Babbitt, ).…”

Section: How Slow Is Rubisco?mentioning

confidence: 99%

Rubisco is not really so bad

Bathellier

Tcherkez

Lorimer

et al. 2018

Plant Cell & Environment

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Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is the most widespread carboxylating enzyme in autotrophic organisms. Its kinetic and structural properties have been intensively studied for more than half a century. Yet important aspects of the catalytic mechanism remain poorly understood, especially the oxygenase reaction. Because of its relatively modest turnover rate (a few catalytic events per second) and the competitive inhibition by oxygen, Rubisco is often viewed as an inefficient catalyst for CO fixation. Considerable efforts have been devoted to improving its catalytic efficiency, so far without success. In this review, we re-examine Rubisco's catalytic performance by comparison with other chemically related enzymes. We find that Rubisco is not especially slow. Furthermore, considering both the nature and the complexity of the chemical reaction, its kinetic properties are unremarkable. Although not unique to Rubisco, oxygenation is not systematically observed in enolate and enamine forming enzymes and cannot be considered as an inevitable consequence of the mechanism. It is more likely the result of a compromise between chemical and metabolic imperatives. We argue that a better description of Rubisco mechanism is still required to better understand the link between CO and O reactivity and the rationale of Rubisco diversification and evolution.

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“…The growth of wild-type (black curve), DmurI (red curve) and murI gene complemented strains (mustard curve) supplemented with 10 mM D-alanine. D-amino acid transaminase (D-AAT) from Mycobacterium smegmatis 207 for many enzymes is now well recognized (O'Brien and Herschlag, 1999;Khersonsky et al, 2006;Atkins, 2015).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of a newly identified d‐amino acid transaminase in Mycobacterium smegmatis complements glutamate racemase deletion

Mortuza

Aung

Taiaroa

et al. 2017

Molecular Microbiology

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Glutamate racemase (MurI) has been proposed as a target for anti-tuberculosis drug development based on the inability of ΔmurI mutants of Mycobacterium smegmatis to grow in the absence of d-glutamate. In this communication, we identify ΔmurI suppressor mutants that are detected during prolonged incubation. Whole genome sequencing of these ΔmurI suppressor mutants identified the presence of a SNP, located in the promoter region of MSMEG_5795. RT-qPCR and transcriptional fusion analyses revealed that the ΔmurI suppressor mutant overexpressed MSMEG_5795 14-fold compared to the isogenic wild-type. MSMEG_5795, which is annotated as 4-amino-4-deoxychorismate lyase (ADCL) but which also has homology to d-amino acid transaminase (d-AAT), was expressed, purified and found to have d-AAT activity and to be capable of producing d-glutamate from d-alanine. Consistent with its d-amino acid transaminase function, overexpressed MSMEG_5795 is able to complement both ΔmurI deletion mutants and alanine racemase (Δalr) deletion mutants, thus confirming a multifunctional role for this enzyme in M. smegmatis.

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Biological messiness vs. biological genius: Mechanistic aspects and roles of protein promiscuity

Cited by 41 publications

References 73 publications

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity

Rubisco is not really so bad

Overexpression of a newly identified d‐amino acid transaminase in Mycobacterium smegmatis complements glutamate racemase deletion

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