Divergent Evolution of Ligand Binding in the <i>o</i>-Succinylbenzoate Synthase Family

Odokonyero, Denis; Sugadev, R.; Lopez, Mariana S.; Bonanno, J.B.; Ozerova, Nicole; Woodard, DaNae R; Machala, Benjamin W.; Swaminathan, Subramanyam; Burley, S.K.; Almo, Steven C.; Glasner, Margaret E.

doi:10.1021/bi401176d

Cited by 14 publications

(42 citation statements)

References 46 publications

(189 reference statements)

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“…Given the large structural changes associated with loss of quaternary structure and indels, the divergence of OSBS enzymes is probably irreversible. Indeed, mutagenesis to swap amino acids at homologous positions in E. coli and T. fusca OSBS enzymes was deleterious (52). This is similar to the observed mutational epistasis in other proteins, such as the glucocorticoid receptors, although structure, not specificity, has diverged among monomeric OSBSs (56).…”

Section: Discussionmentioning

confidence: 57%

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Loss of quaternary structure is associated with rapid sequence divergence in the OSBS family

Odokonyero

Sakai

Patskovsky³

et al. 2014

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

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The rate of protein evolution is determined by a combination of selective pressure on protein function and biophysical constraints on protein folding and structure. Determining the relative contributions of these properties is an unsolved problem in molecular evolution with broad implications for protein engineering and function prediction. As a case study, we examined the structural divergence of the rapidly evolving o-succinylbenzoate synthase (OSBS) family, which catalyzes a step in menaquinone synthesis in diverse microorganisms and plants. On average, the OSBS family is much more divergent than other protein families from the same set of species, with the most divergent family members sharing <15% sequence identity. Comparing 11 representative structures revealed that loss of quaternary structure and large deletions or insertions are associated with the family's rapid evolution. Neither of these properties has been investigated in previous studies to identify factors that affect the rate of protein evolution. Intriguingly, one subfamily retained a multimeric quaternary structure and has small insertions and deletions compared with related enzymes that catalyze diverse reactions. Many proteins in this subfamily catalyze both OSBS and N-succinylamino acid racemization (NSAR). Retention of ancestral structural characteristics in the NSAR/OSBS subfamily suggests that the rate of protein evolution is not proportional to the capacity to evolve new protein functions. Instead, structural features that are conserved among proteins with diverse functions might contribute to the evolution of new functions.enolase superfamily | protein structure | protein structure-function relationships I nvestigating the causes and effects of protein sequence divergence is the key to identifying properties that enable proteins to evolve new functions. Previous studies found that constraints imposed by biophysical properties such as protein folding and stability, translational accuracy, and interactions with other proteins make a large contribution to the rate of protein evolution (1-11). However, the relative contributions of biophysical properties versus functional constraints is an open question (2). Given that the rate of protein evolution varies over several orders of magnitude, the evolutionary rate of each protein is probably determined by a unique blend of biophysical and functional constraints (12-15). Thus, the evolutionary simulations and statistical analyses of large protein datasets that comprise the primary focus of this field need to be supplemented with case studies.Here, we present the extraordinarily diverse o-succinylbenzoate synthase (OSBS) family as such a case study. The OSBS family belongs to the enolase superfamily, a group of evolutionarily related protein families that have a common fold but catalyze diverse reactions (16). The rate of sequence divergence in the OSBS family is much faster than other families in the enolase superfamily. For example, the average pairwise amino acid sequence identity of OSBSs fr...

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Section: Discussionmentioning

confidence: 57%

“…To date, our data do not support this idea, although experiments have been limited to a small number of active-site residues. Mutations of active-site residues have similar effects in E. coli OSBS, T. fusca OSBS, and P. putida mandelate racemase (MR), reducing k cat /K M by ∼10-to 500-fold (52)(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Loss of quaternary structure is associated with rapid sequence divergence in the OSBS family

Odokonyero

Sakai

Patskovsky³

et al. 2014

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

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“…Intramolecular epistasis is generally defined as a non-additive effect on protein function arising from multiple substitutions, which can then lead to inconsistent phenotypic effects from the same substitution in different genotypic backgrounds (e.g. [28]). This phenomenon has been experimentally demonstrated to constrain several protein evolutionary pathways including increased oxygen affinity in high-altitude haemoglobins [29], bacterial antibiotic resistance [27] and glucocorticoid receptor specificity [30].…”

Section: Discussionmentioning

confidence: 99%

Epistatic interactions influence terrestrial–marine functional shifts in cetacean rhodopsin

Dungan

Chang

2017

Proc. R. Soc. B.

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Like many aquatic vertebrates, whales have blue-shifting spectral tuning substitutions in the dim-light visual pigment, rhodopsin, that are thought to increase photosensitivity in underwater environments. We have discovered that known spectral tuning substitutions also have surprising epistatic effects on another function of rhodopsin, the kinetic rates associated with light-activated intermediates. By using absorbance spectroscopy and fluorescence-based retinal release assays on heterologously expressed rhodopsin, we assessed both spectral and kinetic differences between cetaceans (killer whale) and terrestrial outgroups (hippo, bovine). Mutation experiments revealed that killer whale rhodopsin is unusually resilient to pleiotropic effects on retinal release from key blue-shifting substitutions (D83N and A292S), largely due to a surprisingly specific epistatic interaction between D83N and the background residue, S299. Ancestral sequence reconstruction indicated that S299 is an ancestral residue that predates the evolution of blue-shifting substitutions at the origins of Cetacea. Based on these results, we hypothesize that intramolecular epistasis helped to conserve rhodopsin's kinetic properties while enabling blue-shifting spectral tuning substitutions as cetaceans adapted to aquatic environments. Trade-offs between different aspects of molecular function are rarely considered in protein evolution, but in cetacean and other vertebrate rhodopsins, may underlie multiple evolutionary scenarios for the selection of specific amino acid substitutions.

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“…The varying levels of hydratase and MSAD activities observed in MSAD and the MSAD homologues are reminiscent of the o -succinylbenzoate synthase/N-succinylamino acid racemase (OSBS/NSAR) activities for members in one branch of the OSBS family in the enolase superfamily [49,50]. Both activities have a biological purpose: OSBS catalyzes a dehydration reaction to form o -succinylbenzoate in the menaquinone biosynthetic pathway and NSAR converts D-amino acids to L-amino acids via the N-succinylated derivatives [51].…”

Section: Characterization Of Five New Msad Homologuesmentioning

confidence: 99%

Identification and characterization of new family members in the tautomerase superfamily: Analysis and implications

Huddleston¹,

Burks²,

Whitman³

2014

Archives of Biochemistry and Biophysics

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Tautomerase superfamily members are characterized by a β–α–β building block and a catalytic amino terminal proline. 4-oxalocrotonate tautomerase (4-OT) and malonate semialdehyde decarboxylase (MSAD) are the title enzymes of two of the five known families in the superfamily. Two recent developments in these families indicate that there might be more metabolic diversity in the tautomerase superfamily than previously thought. 4-OT homologues have been identified in three biosynthetic pathways, whereas all previously characterized 4-OTs are found in catabolic pathways. In the MSAD family, homologues have been characterized that lack decarboxylase activity, but have a modest hydratase activity using 2-oxo-3-pentynoate. This observation stands in contrast to the first characterized MSAD, which is a proficient decarboxylase and a less efficient hydratase. The hydratase activity was thought to be a vestigial and promiscuous activity. However, this recent discovery suggests that the hydratase activity might reflect a new activity in the MSAD family for an unknown substrate. These discoveries open up new avenues of research in the tautomerase superfamily.

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Divergent Evolution of Ligand Binding in the o-Succinylbenzoate Synthase Family

Cited by 14 publications

References 46 publications

Loss of quaternary structure is associated with rapid sequence divergence in the OSBS family

Loss of quaternary structure is associated with rapid sequence divergence in the OSBS family

Epistatic interactions influence terrestrial–marine functional shifts in cetacean rhodopsin

Identification and characterization of new family members in the tautomerase superfamily: Analysis and implications

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