Enzyme Evolution Explained (Sort Of)

Am, Dean; Gb, Golding

doi:10.1142/9789814447331_0002

Cited by 19 publications

(20 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Beginning graduate students studying a novel protein learn that to knock out function, the best places to mutate the protein are the most conserved sites. This relationship is sometimes viewed as almost a tautology, so conserved sites are believed to be functionally important by definition, but surveys of many proteins have revealed that residue conservation can be well predicted based on a combination of distance from active sites and distance from the hydrophobic core (Dean and Golding, 2000). An important development based on this relationship has been that changes in residue conservation can be viewed (again, sometimes tautologically) as strong predictors of changes in the function of those residues.…”

Section: Introductionmentioning

confidence: 99%

Context Dependence and Coevolution Among Amino Acid Residues in Proteins

Wang¹,

Pollock²

2005

Methods in Enzymology

View full text Add to dashboard Cite

As complete genomes accumulate and the generation of genomic biodiversity proceeds at an accelerating pace, the need to understand the interaction between sequence evolution and protein structure and function rises in prominence. The pattern and pace of substitutions in proteins can provide important clues to functional importance, functional divergence, and adaptive response. Coevolution between amino acid residues and the context dependence of the evolutionary process are often ignored, however, because of their complexity, but they are critical for the accurate interpretation of reconstructed evolutionary events. Because residues interact with one another, and because the effect of substitutions can depend on the structural and physiological environment in which they occur, an accurate science of evolutionary functional genomics and a complete understanding of selection in proteins require a better understanding of how context dependence affects protein evolution. Here, we present new evidence from vertebrate cytochrome oxidase sequences that pairwise coevolutionary interactions between protein residues are highly dependent on tertiary and secondary structure. We also discuss theoretical predictions that impinge on our expectations of how protein residues may interact over long distances because of their shared need to maintain protein stability.

show abstract

Section: Introductionmentioning

confidence: 99%

Context Dependence and Coevolution Among Amino Acid Residues in Proteins

Wang¹,

Pollock²

2005

Methods in Enzymology

View full text Add to dashboard Cite

show abstract

“…Others have also described catalytic residues and their local environment as highly conserved (Zvelebil et al 1987;Dean and Golding 2000;Bartlett et al 2002). The concept of an "environment" that we analogize with our ∼30 Å diameter most-conserved Zone 9 was suggested by reports indicating that more effective functional change (enantioselectivity, substrate specificity, new catalytic activity) are associated with amino acid substitution close to catalytic sites.…”

Section: Discussionmentioning

confidence: 81%

Concentration of Specific Amino Acids at the Catalytic/Active Centers of Highly-Conserved “Housekeeping” Enzymes of Central Metabolism in Archaea, Bacteria and Eukaryota: Is There a Widely Conserved Chemical Signal of Prebiotic Assembly?

Pollack

Pan

Pearl

2010

Orig Life Evol Biosph

View full text Add to dashboard Cite

In alignments of 1969 protein sequences the amino acid glycine and others were found concentrated at most-conserved sites within approximately 15 A of catalytic/active centers (C/AC) of highly conserved kinases, dehydrogenases or lyases of Archaea, Bacteria and Eukaryota. Lysine and glutamic acid were concentrated at least-conserved sites furthest from their C/ACs. Logistic-regression analyses corroborated the "movement" of glycine towards and lysine away from their C/ACs: the odds of a glycine occupying a site were decreased by 19%, while the odds for a lysine were increased by 53%, for every 10 A moving away from the C/AC. Average conservation of MSA consensus sites was highest surrounding the C/AC and directly decreased in transition toward model's peripheries. Findings held with statistical confidence using sequences restricted to individual Domains or enzyme classes or to both. Our data describe variability in the rate of mutation and likelihoods for phylogenetic trees based on protein sequence data and endorse the extension of substitution models by incorporating data on conservation and distance to C/ACs rather than only using cumulative levels. The data support the view that in the most-conserved environment immediately surrounding the C/AC of taxonomically distant and highly conserved essential enzymes of central metabolism there are amino acids whose identity and degree of occupancy is similar to a proposed amino acid set and frequency associated with prebiotic evolution.

show abstract

“…ESF analyses estimate rates within a window, normalize the local rates by the average rate, smooth the rates to detect ECRs, and then rank the ECRs by the rate of the most slowly evolving window. This combination of algorithms distinguishes the method from similar approaches that either require structures (7,8), do not predict or rank ECRs, or separately estimate rates for each position (9). One key assumption we make is that of a strong correlation of rates in sites that are close in the alignment.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6]. A more recent application of estimating rate variation within proteins has been the inference of structural and functional constraints (7)(8)(9).…”

mentioning

confidence: 99%

Inference of functional regions in proteins by quantification of evolutionary constraints

Simon

Stone

Sidow

2002

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

View full text Add to dashboard Cite

Likelihood estimates of local rates of evolution within proteins reveal that selective constraints on structure and function are quantitatively stable over billions of years of divergence. The stability of constraints produces an intramolecular clock that gives each protein a characteristic pattern of evolutionary rates along its sequence. This pattern allows the identification of constrained regions and, because the rate of evolution is a quantitative measure of the strength of the constraint, of their functional importance. We show that results from such analyses, which require only sequence alignments, are consistent with experimental and mutational data. The methodology has significant predictive power and may be used to guide structure-function studies for any protein represented by a modest number of homologs in sequence databases.T he principle that the rate of molecular evolution is inversely correlated with the strength of selective constraints has long been known (1, 2). The average evolutionary rate of a protein reflects the overall importance of the protein for organismal functions, whereas rate variation within the protein reflects intramolecular differences in structural and functional constraints. Intramolecular rate variation has been the subject of many studies focused on devising more realistic models of sequence evolution that do not assume rate constancy among sites (e.g., refs. 3-6). A more recent application of estimating rate variation within proteins has been the inference of structural and functional constraints (7-9).To identify evolutionarily constrained regions (ECRs) we devised a general approach to inferring rate variation within proteins. We construct a multiple sequence alignment of orthologs and͞or closely related paralogs and build the maximum likelihood tree. Holding the branching structure of the tree fixed, we then calculate the number of substitutions in each window of a fixed width over the entire alignment. The ''relative rate'' in the window is obtained by dividing the number of substitutions per site in the window by the average of all windows. Plotting the windows' relative rates as a function of their position generates a rate profile (RP), and a heuristic algorithm automatically identifies ECRs and ranks them by their rate of evolution. This approach allows us to infer both the existence of constrained regions in a protein and, because the rate of evolution is a quantitative measure of the strength of the constraint, the relative importance of the identified region.Our method requires only a multiple sequence alignment and is sufficiently powerful to allow analyses involving a relatively small number of fairly closely related sequences. It enables us (i) to use sequences for which the quality of the alignment over most its length is indisputably robust, and (ii) to use alignments of orthologs and closely related paralogs for which conservation of structural and functional constraints can be reasonably assumed. We show below that the method identifies known domains wit...

show abstract

Enzyme Evolution Explained (Sort Of)

Cited by 19 publications

References 9 publications

Context Dependence and Coevolution Among Amino Acid Residues in Proteins

Context Dependence and Coevolution Among Amino Acid Residues in Proteins

Concentration of Specific Amino Acids at the Catalytic/Active Centers of Highly-Conserved “Housekeeping” Enzymes of Central Metabolism in Archaea, Bacteria and Eukaryota: Is There a Widely Conserved Chemical Signal of Prebiotic Assembly?

Inference of functional regions in proteins by quantification of evolutionary constraints

Contact Info

Product

Resources

About