Evolution of oligomeric state through allosteric pathways that mimic ligand binding

Perica, Tina; Kondo, Yasumasa; Tiwari, Sandhya; McLaughlin, Stephen H.; Kemplen, Katherine R.; Zhang, Xiuwei; Steward, Annette; Reuter, Nathalie; Clarke, Jane; Teichmann, Sarah A.

doi:10.1126/science.1254346

Cited by 65 publications

(69 citation statements)

References 67 publications

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“…Altogether, the binding of PRPP and nucleotides to PyrR is similar to that of type I phosphoribosyltransferases. PyrR from B. caldolyticus has been proposed to exist as a dimer or tetramer (337,339,340), although B. subtilis PyrR has been shown to exist in a hexameric state (341). The dimerization pattern of PyrR is different from that of type I phosphoribosyltransferases, and the RNA-binding activity of PyrR has been proposed to be due to the exposure of a region of basic amino acid residues in the dimer.…”

Section: Regulation Of Pyrimidine Metabolism By the Rna-binding Pyrr mentioning

confidence: 96%

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Hove‐Jensen

Andersen

Kilstrup

et al. 2017

Microbiol Mol Biol Rev

157

187

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SUMMARY Phosphoribosyl diphosphate (PRPP) is an important intermediate in cellular metabolism. PRPP is synthesized by PRPP synthase, as follows: ribose 5-phosphate + ATP → PRPP + AMP. PRPP is ubiquitously found in living organisms and is used in substitution reactions with the formation of glycosidic bonds. PRPP is utilized in the biosynthesis of purine and pyrimidine nucleotides, the amino acids histidine and tryptophan, the cofactors NAD and tetrahydromethanopterin, arabinosyl monophosphodecaprenol, and certain aminoglycoside antibiotics. The participation of PRPP in each of these metabolic pathways is reviewed. Central to the metabolism of PRPP is PRPP synthase, which has been studied from all kingdoms of life by classical mechanistic procedures. The results of these analyses are unified with recent progress in molecular enzymology and the elucidation of the three-dimensional structures of PRPP synthases from eubacteria, archaea, and humans. The structures and mechanisms of catalysis of the five diphosphoryltransferases are compared, as are those of selected enzymes of diphosphoryl transfer, phosphoryl transfer, and nucleotidyl transfer reactions. PRPP is used as a substrate by a large number phosphoribosyltransferases. The protein structures and reaction mechanisms of these phosphoribosyltransferases vary and demonstrate the versatility of PRPP as an intermediate in cellular physiology. PRPP synthases appear to have originated from a phosphoribosyltransferase during evolution, as demonstrated by phylogenetic analysis. PRPP, furthermore, is an effector molecule of purine and pyrimidine nucleotide biosynthesis, either by binding to PurR or PyrR regulatory proteins or as an allosteric activator of carbamoylphosphate synthetase. Genetic analyses have disclosed a number of mutants altered in the PRPP synthase-specifying genes in humans as well as bacterial species.

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Section: Regulation Of Pyrimidine Metabolism By the Rna-binding Pyrr mentioning

confidence: 96%

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Hove‐Jensen

Andersen

Kilstrup

et al. 2017

Microbiol Mol Biol Rev

157

187

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“…For many proteins, these interactions are enhanced or suppressed by allosteric networks that couple distant regions together (1). The mechanisms by which these networks function are just starting to be understood (2)(3)(4), and many of the important details have yet to be uncovered. In particular, the role of intrinsic protein motion and kinetics remains particularly poorly characterized.…”

mentioning

confidence: 99%

Allosteric switch regulates protein–protein binding through collective motion

Smith

Ban

Pratihar

et al. 2016

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

105

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Many biological processes depend on allosteric communication between different parts of a protein, but the role of internal protein motion in propagating signals through the structure remains largely unknown. Through an experimental and computational analysis of the ground state dynamics in ubiquitin, we identify a collective global motion that is specifically linked to a conformational switch distant from the binding interface. This allosteric coupling is also present in crystal structures and is found to facilitate multispecificity, particularly binding to the ubiquitin-specific protease (USP) family of deubiquitinases. The collective motion that enables this allosteric communication does not affect binding through localized changes but, instead, depends on expansion and contraction of the entire protein domain. The characterization of these collective motions represents a promising avenue for finding and manipulating allosteric networks.allostery | protein dynamics | concerted motion | relaxation dispersion | nuclear magnetic resonance I ntermolecular interactions are one of the key mechanisms by which proteins mediate their biological functions. For many proteins, these interactions are enhanced or suppressed by allosteric networks that couple distant regions together (1). The mechanisms by which these networks function are just starting to be understood (2-4), and many of the important details have yet to be uncovered. In particular, the role of intrinsic protein motion and kinetics remains particularly poorly characterized. A number of structural ensembles representing ubiquitin motion have been recently proposed (5-9). Additionally, it has been suggested that through motion at the binding interface, its free state visits the same conformations found in complex with its many binding partners (5, 10). However, it remains an unanswered question if the dynamics that enable this multispecificity are only clustered around the canonical binding interface or whether this motion is allosterically coupled to the rest of the protein, especially given the presence of motion at distal sites (11). ResultsTo answer this question and to provide a detailed structural picture of the underlying mechanism, we applied recently developed high-power relaxation dispersion (RD) experiments (12, 13) to both the backbone amide proton ( 1 H N ) and nitrogen ( 15 N) nuclei of ubiquitin. This survey yielded a nearly twofold increase in the number of nuclei where RD had been previously observed (11)(12)(13)(14) (from 17 to 31; Fig. 1A and Fig. S1). When fit individually, the full set of backbone and side-chain nuclei shows a consistent time scale of motion [exchange lifetime (τ ex ) = 55 μs; Fig. 1B]. Furthermore, the nuclei showing exchange are spread throughout the structure (Fig. 1C). Put together, these data suggest that the motions are not independent but share a common molecular mechanism.To determine whether the RD data could be modeled using a single collective motion, we developed a computational method to take a set of molecu...

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“…(A) Select extant sequences: Commonly, homologous sequences were retrieved from databases like GenBank of the NCBI or UniProtKB of the EBI (see, for example, Boussau et al, 2008;Gaucher et al, 2008;Finnigan et al, 2012;Voordeckers et al, 2012;Bar-Rogovsky et al, 2013;Risso et al, 2013;Perica et al, 2014), most often with the help of BLAST (Altschul et al, 1990). If the number of hits was very large, highly similar sequences were eliminated by using CD-HIT (Li and Godzik, 2006) to create a set of sequences with 30-90% identical residues (Bar-Rogovsky et al, 2013).…”

Section: Current Software Protocols For Asrmentioning

confidence: 99%

“…Moreover, the contribution of gene duplications to the evolution of modern enzymes (Voordeckers et al, 2012) and the sophistication of enzyme complexes were studied by means of ASR (Bridgham et al, 2006;Perica et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Ancestral protein reconstruction: techniques and applications

Merkl

Sterner

2016

Biological Chemistry

131

104

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Ancestral sequence reconstruction (ASR) is the calculation of ancient protein sequences on the basis of extant ones. It is most powerful in combination with the experimental characterization of the corresponding proteins. Such analyses allow for the study of problems that are otherwise intractable. For example, ASR has been used to characterize ancestral enzymes dating back to the Paleoarchean era and to deduce properties of the corresponding habitats. In addition, the historical approach underlying ASR enables the identification of amino acid residues key to protein function, which is often not possible by only comparing extant proteins. Along these lines, residues responsible for the spectroscopic properties of protein pigments were identified as well as residues determining the binding specificity of steroid receptors. Further applications are studies related to the longevity of mutations, the contribution of gene duplications to enzyme functionalization, and the evolution of protein complexes. For these applications of ASR, we discuss recent examples; moreover, we introduce the basic principles of the underlying algorithms and present state-of-the-art protocols.

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Evolution of oligomeric state through allosteric pathways that mimic ligand binding

Cited by 65 publications

References 67 publications

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Allosteric switch regulates protein–protein binding through collective motion

Ancestral protein reconstruction: techniques and applications

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