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PubMed2006

Testing for spatial clustering of amino acid replacements within protein tertiary structure.

Widely used models of protein evolution ignore protein structure. Therefore, these models do not predict spatial clustering of amino acid replacements with respect to tertiary structure. One formal and biologically implausible possibility is that there is no tendency for amino acid replacements to be spatially clustered during evolution. An alternative to this is that amino acid replacements are spatially clustered and this spatial clustering can be fully explained by a tendency for similar rates of amino acid replacement at sites that are nearby in protein tertiary structure. A third possibility is that the amount of clustering exceeds that which can be explained solely on the basis of independently evolving protein sites with spatially clustered replacement rates. We introduce two simple and not very parametric hypothesis tests that help distinguish these three possibilities. We then apply these tests to 273 homologous protein families. The null hypothesis of no spatial clustering is rejected for 102 of 273 families. The explanation of spatially clustered rates but independent change among sites is rejected for 43 families. These findings need to be reconciled with the common practice of basing evolutionary inferences on models that assume independent change among sites.

Amino Acid Substitution↗
PubMed1975

The appearance of new structures and functions in proteins during evolution.

The likelihood of a de novo generation of classes of efficient proteins through neoformation of DNA, through modification of expressed DNA, and through modification of nonexpressed DNA is examined. So is the likelihood that newly formed inefficient enzymes be turned into efficient enzymes. The conclusions are that neither gene duplicates nor dormant genes represent promising materials for a de novo generation of protein classes, that (with exceptions) such generation is unlikely to have taken place in recent evolution, that new structural genes must nearly consistently derive from preexisting structural genes, and that new functions can be evolved only on the basis of old proteins. Conditions of protein evolution in prokaryotes suggest that the saltatory formation of protein classes is as unlikely in prokaryotes as in eukaryotes. Data on the history of a few protein classes are reviewed to illustrate the preceding inferences. The analysis leads to the hypothesis that most protein classes originated before the major elements of the translation apparatus of modern cells were fully evolved. If simple sequence DNA is turned into structural genes by evolution, this process (again with exceptions) is considered to have taken place only at that very remote period. A polyphyletic origin of proteins is thought to date back to the same era. It is proposed that the development of genic multiplicity and of marked structural and functional diversity of proteins may have come about in the earliest cells primarily through the independent generation of structurally different polymerases in different protocells, followed by cell conjugation and the subsequent use by enriched cells of supernumerary types of polymerase for evolving further functions. Functional growth, as it took place at early times, is briefly discussed as well as functional change. The foundations for new functional developments in old proteins are analyzed. In considering the evolutionary recovery of lost functions, aspects of cell differentiation and gene regulation are linked with the evolutionary picture. The distinction between eurygenic and stemogenic control of gene activity is used. Next to gene deletion, cell and tissue deletion is held to be an event of general evolutionary significance, through cell and tissue origination that presumably accompanies the restoration of a lost molecular function.

Amino Acids↗
PubMed2001

Genotype-phenotype linkage for directed evolution and screening of combinatorial protein libraries.

The technologies for screening peptide and protein libraries for studies in the fields of directed protein evolution and functional genomics have advanced with astonishing speed. For screening of functional proteins, three technologies are required: (i) the construction of a gene library (genotype), (ii) the establishment of a linkage between each protein (phenotype) and its encoding gene (genotype), and (iii) the selection of desired proteins (phenotype) from the library. This review highlights the genotype-phenotype linkage technologies, which can be classified into three types; that is, cell-type linkage, virus-type linkage, and array-type linkage methods. These methods are summarized, and their advantages and disadvantages are discussed.

Animals↗
PubMed2001

A test of amino acid reversibility.

In studies of molecular evolution, the assumption that protein evolution is reversible has often been made, but rarely tested. Here we use a large set of orthologous murid protein coding sequences to perform a simple test of reversibility, and find no evidence to reject the assumption of reversibility in protein evolution.

Amino Acid Substitution↗
PubMed2002

Evolution of protein synthesis in a lattice model of replicators.

The traditional chemical-kinetics approach to the study of prebiotic evolution cannot explain the evolution of protein synthesis in a homogeneous population of self-replicating molecules, because the invasion of a resident population of simpler, template-directed replicators by mutant protein-assisted replicators is deemed impossible. Approaching this problem in a spatial cellular automaton framework, we argue here that in such a setting evolution of protein synthesis is a likely event. In addition, we show that the onset of invasion may be viewed as a nonequilibrium phase transition, that can be characterized quantitatively by a set of critical exponents.

Models, Biological↗
PubMed1992

The evolution of protein domains and the organizational complexities of metazoans.

There is an increasingly heated debate on the very existence of a 'universe of exons' and on the types of genomes that existed after the RNA world. What has been lost in the excitement are the biological issues that relate to the rapid emergence of phenotypic novelties. These issues can be examined by integrating data on protein domains and genomic evolution with the geochemical and palaeontological records.

Animals↗
PubMed2006

MANET: tracing evolution of protein architecture in metabolic networks.

BACKGROUND: Cellular metabolism can be characterized by networks of enzymatic reactions and transport processes capable of supporting cellular life. Our aim is to find evolutionary patterns and processes embedded in the architecture and function of modern metabolism, using information derived from structural genomics. DESCRIPTION: The Molecular Ancestry Network (MANET) project traces evolution of protein architecture in biomolecular networks. We describe metabolic MANET, a database that links information in the Structural Classification of Proteins (SCOP), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and phylogenetic reconstructions depicting the evolution of protein fold architecture. Metabolic MANET literally 'paints' the ancestries of enzymes derived from rooted phylogenomic trees directly onto over one hundred metabolic subnetworks, enabling the study of evolutionary patterns at global and local levels. An initial analysis of painted subnetworks reveals widespread enzymatic recruitment and an early origin of amino acid metabolism. CONCLUSION: MANET maps evolutionary relationships directly and globally onto biological networks, and can generate and test hypotheses related to evolution of metabolism. We anticipate its use in the study of other networks, such as signaling and other protein-protein interaction networks.

Computer Graphics↗
PubMed1997

Chimeric proteins can exceed the sum of their parts: implications for evolution and protein design.

Chimeric analogs derived from pairs of homologous proteins routinely exhibit activities found in one or both parents. We describe chimeras of two glycoprotein hormones, human chorionic gonadotropin (hCG) and human follitropin (hFSH), that exhibit activity unique to a third family member, human thyrotropin (hTSH). The results show that biological activity can be separated from hormone-specific amino acid residues. This is consistent with a model for the evolution of homologous ligand-receptor pairs involving gene duplication and the creation of inhibitory determinants that restrict binding. Disruption of these determinants can unmask activities characteristic of other members of a protein family. Combining portions of two ligands to create analogs with properties of a third family member can facilitate identifying key determinants of protein-protein interaction and may be a useful strategy for creating novel therapeutics. In the case of the glycoprotein hormones, this showed that two different hormone regions (i.e., the seat-belt and the intersubunit groove) appear to limit inappropriate contacts with receptors for other members of this family. These observations also have important caveats for chimera-based protein design because an unexpected gain of function may limit the therapeutic usefulness of some chimeras.

Amino Acid Sequence↗
PubMed2003

Non-animal origin of animal thioredoxin reductases: implications for selenocysteine evolution and evolution of protein function through carboxy-terminal extensions.

Thioredoxin reductase (TR) and thioredoxin constitute a major cellular redox system present in all organisms. In contrast to a single form of thioredoxin, there are two TR types: One (bacterial type or small TR) is present in bacteria, archaea, plants, and most unicellular eukaryotes, whereas the second (animal or large TR) is only found in animals and typically contains a carboxy-terminal penultimate selenocysteine encoded by TGA. Surprisingly, we detected sequences of large TRs in various unicellular eukaryotes. Moreover, green algae Chlamydomonas reinhardtii had both small and large TRs, with the latter being a selenoprotein, but no examples of horizontal gene transfer from animals to the green algae could be detected. In addition, phylogenetic analyses revealed that large TRs formed a subgroup of lower eukaryotic glutathione reductases (GRs). The data suggest that the large TR evolved in a lower eukaryote capable of selenocysteine insertion rather than in an animal. The enzyme appeared to evolve by a carboxy-terminal extension of GR such that the resulting carboxy-terminal glutathionelike peptide became an intramolecular substrate for GR and a reductant for thioredoxin. Subsequently, small TRs were lost in an organism that gave rise to animals, large TRs were lost in plants and fungi, and selenocysteine/cysteine replacements took place in some large TRs. Our data implicate carboxy-terminal extension of proteins as a general mechanism of evolution of new protein function.

Amino Acid Sequence↗
PubMed2004

A novel method for estimating ancestral amino acid composition and its application to proteins of the Last Universal Ancestor.

MOTIVATION: Knowledge of how proteomic amino acid composition has changed over time is important for constructing realistic models of protein evolution and increasing our understanding of molecular evolutionary history. The proteomic amino acid composition of the Last Universal Ancestor (LUA) of life is of particular interest, since that might provide insight into the early evolution of proteins and the nature of the LUA itself. RESULTS: We introduce a method to estimate ancestral amino acid composition that is based on expectation-maximization. On simulated data, the approach was found to be very effective in estimating ancestral amino acid composition, with accuracy improving as the number of residues in the dataset was increased. The method was then used to infer the amino acid composition of a set of proteins in the LUA. In general, as compared with the modern protein set, LUA proteins were found to be richer in amino acids that are believed to have been most abundant in the prebiotic environment and poorer in those believed to have been unavailable or scarce. Additionally, we found the inferred amino acid composition of this protein set in the LUA to be more similar to the observed composition of the same set in extant thermophilic species than in extant mesophilic species, supporting the idea that the LUA lived in a thermophilic environment. AVAILABILITY: The program is available at http://compbio.cs.princeton.edu/ancestralaa

Algorithms↗
PubMed2006

In vitro evolution of proteins.

Consecutive rounds of diversification and selection of the fittest is believed to be the main driving force for the evolution of life. For the evolution of life to proceed, all living cells are surrounded by a lipid bilayer that separates their own genes from the external environment and from those of other organisms. In this way, the genetic information of an individual is replicated on the basis of their phenotype; thus the enrichment of the fittest will occur. Hence, evolution is based on linkage between genotype and phenotype owing to the surrounding of the genetic material with a barrier. The linkage between genotype and phenotype is also known to be essential for the directed evolution of proteins. Indeed, systems for molecular evolution, including phage display, ribosome display, and in vitro compartmentalization, all satisfy this requirement in different ways. These systems have been shown to be powerful tools for high-throughput screening for the functions of proteins, screening as many as <10(12) molecules in 1 d. These selection systems in combination with various gene libraries yield proteins with improved or altered biophysical properties, and may even allow the generation of proteins with novel functions.

Amino Acid Sequence↗
PubMedDate not supplied

Neuroglobin and cytoglobin: genes, proteins and evolution.

Hemoglobin and myoglobin are oxygen transport and storage proteins of most vertebrates. Neuroglobin (Ngb) and cytoglobin (Cygb)--two recent additions to the vertebrate globin superfamily--have still disputed functions. Combining the data from all available resources, we investigate the evolution of these novel globins. Both Ngb and Cygb show little sequence variation in vertebrate evolution, suggesting conserved structures and functions, and an important role in the animal's metabolism. Exon-intron patterns remained unchanged in Ngb and Cygb, with the exception of the addition of a 3' exon to Cygb early in mammalian evolution. In phylogenetic analyses, Ngb forms a common branch with globin X, another recently identified globin with undefined function in lower vertebrates, and with some invertebrate nerve globins. This shows an early divergence of this branch in animal evolution. Cygb is related to myoglobin, and associated with an eye-specific globin from birds. The pattern of globin evolution shows that proteins with clear respiratory roles evolved independently from intracellular globins with uncertain functions. This result suggests either multiple independent functional changes or a yet undefined respiratory role of tissue globins like Ngb and Cygb.

Amino Acid Sequence↗
PubMed1995

Prolines and amyloidogenicity in fragments of the Alzheimer's peptide beta/A4.

Although it is well accepted that the structure of amyloid fibrils is dominated by some form of antiparallel beta-sheet, there are few details on the secondary structural arrangements of the constituent peptides and how these peptides pack together in the fibril. We describe here the use of scanning proline mutagenesis to map the secondary structural roles of each residue in amyloidogenic peptide fragments of the Alzheimer's amyloid peptide beta/A4. In two series of fragments related to residues 15-23 and 12-26 of beta/A4, we show that Pro replacement of any residue in the amyloidogenic sequence LVFFAED, corresponding to residues 17-23, leads to essentially complete loss of fibril formation and to excellent peptide solubility. Since peptidyl-prolyl bonds are incapable of forming standard extended chain conformations, the results suggest that residues 17-23 make up the beta-sheet core of the fibrils formed by these fragments. In contrast to the proline replacements, alanine substitutions at residues 17, 18, and 20 have no effect on fibril formation, while replacement of Phe19 reduces fibril formation to 15% of the level found for the wild type sequence. Scanning proline mutagenesis should play a useful role in mapping the secondary structural features of larger amyloidogenic peptide sequences, including longer, physiologically relevant forms of beta/A4. In addition, these results suggest explanations for some amyloidogenic effects observed in disease-related peptides and also suggest a possible role for aggregation-inhibiting insertion of prolines in protein evolution and protein design.

Alzheimer Disease↗
PubMed1974

Two types of molecular evolution. Evidence from studies of interspecific hybridization.

To assess the significance of macromolecular sequence differences among species, we compared the serum albumins of 81 pairs of vertebrate species capable of producing viable hybrids. Micro-complement fixation experiments showed that the average difference between the albumins within such pairs was only 3 immunological distance units for placental mammals (31 pairs), but 36 units for frogs (50 pairs). Albumin immunological distance is strongly correlated with other measures of genetic distance, including those made with DNA annealing techniques. It therefore seems likely that mammalian species pairs capable of hybridization are far more similar at the macromolecular sequence level than is the case for most hybridizable frogs. We think the most likely explanation for the marked molecular restriction on hybridization among mammals is that the ratio of regulatory evolution to protein evolution is higher for mammals than for frogs. Mammals may have experienced unusually rapid regulatory evolution; indeed, this could be the factor responsible for their unusually rapid anatomical evolution.

Amino Acid Sequence↗
PubMed2002

Ribosome display: cell-free protein display technology.

Ribosome display is a cell-free system for the in vitro selection of proteins and peptides from large libraries. It uses the principle of coupling individual nascent proteins (phenotypes) to their corresponding mRNA (genotypes), through the formation of stable protein-ribosome-mRNA (PRM) complexes. This permits the simultaneous isolation of a functional nascent protein, through affinity for a ligand, together with the encoding mRNA, which is then converted and amplified as DNA for further manipulation, including repeated cycles or protein expression. Ribosome display has a number of advantages over cell-based systems such as phage display; in particular, it can display very large libraries without the restriction of bacterial transformation. It is also suitable for generating toxic, proteolytically sensitive and unstable proteins, and allows the incorporation of modified amino acids at defined positions. In combination with polymerase chain reaction (PCR)-based methods, mutations can be introduced efficiently into the selected DNA pool in subsequent cycles, leading to continuous DNA diversification and protein selection (in vitro protein evolution). Both prokaryotic and eukaryotic ribosome display systems have been developed and each has its own distinctive features. In this paper, ribosome display systems and their application in selection and evolution of proteins are reviewed.

Cell-Free System↗
PubMed1983

Conservation of physico-chemical amino acid properties during the evolution of proteins.

Based on a similarity ring constructed from a substitution probability matrix, we have analyzed the conservation of some amino acid properties in the evolution of proteins. Refractive index and bulkiness are highly conserved, hydrophobicity and polarity are fairly well conserved while optical rotation appears to be a less relevant property. On the other hand, the analysis of the correspondence between phenotype and genotype shows that the most frequent amino acid substitutions in proteins do not always correspond to the most feasible codon changes. The apparent disagreement between amino acid substitutions in modern proteins and the primordial amino acid-codon assignment is discussed.

Amino Acids↗