Evolution of the arginase fold and functional diversity.
Ontology highlight
ABSTRACT:
SUBMITTER: Dowling DP
PROVIDER: S-EPMC2653620 | biostudies-literature | 2008 Jul
REPOSITORIES: biostudies-literature
Publications
Evolution of the arginase fold and functional diversity.
Dowling D P DP Di Costanzo L L Gennadios H A HA Christianson D W DW
Cellular and molecular life sciences : CMLS 20080701 13
Novel structural superfamilies can be identified among the large number of protein structures deposited in the Protein Data Bank based on conservation of fold in addition to conservation of amino acid sequence. Since sequence diverges more rapidly than fold in protein Evolution, proteins with little or no significant sequence identity are occasionally observed to adopt similar folds, thereby reflecting unanticipated evolutionary relationships. Here, we review the unique alpha/beta fold first obs ...[more]
Similar Datasets
Project description:Hydrophobic cores are fundamental structural properties of proteins typically associated with protein folding and stability; however, how the hydrophobic core shapes protein evolution and function is poorly understood. Here, we investigated the role of conserved hydrophobic cores in fold-A glycosyltransferases (GT-As), a large superfamily of enzymes that catalyze formation of glycosidic linkages between diverse donor and acceptor substrates through distinct catalytic mechanisms (inverting versus retaining). Using hidden Markov models and protein structural alignments, we identify similarities in the phosphate-binding cassette (PBC) of GT-As and unrelated nucleotide-binding proteins, such as UDP-sugar pyrophosphorylases. We demonstrate that GT-As have diverged from other nucleotide-binding proteins through structural elaboration of the PBC and its unique hydrophobic tethering to the F-helix, which harbors the catalytic base (xED-Asp). While the hydrophobic tethering is conserved across diverse GT-A fold enzymes, some families, such as B3GNT2, display variations in tethering interactions and core packing. We evaluated the structural and functional impact of these core variations through experimental mutational analysis and molecular dynamics simulations and find that some of the core mutations (T336I in B3GNT2) increase catalytic efficiency by modulating the conformational occupancy of the catalytic base between "D-in" and acceptor-accessible "D-out" conformation. Taken together, our studies support a model of evolution in which the GT-A core evolved progressively through elaboration upon an ancient PBC found in diverse nucleotide-binding proteins, and malleability of this core provided the structural framework for evolving new catalytic and substrate-binding functions in extant GT-A fold enzymes.
| S-EPMC9364030 | biostudies-literature
Project description:Given the central role fertilization plays in the health and fit-ness of sexually reproducing organisms and the well-known evo-lutionary consequences of sexual selection and sperm compe-tition, knowledge gained by a deeper understanding of sperm(and associated reproductive tissues) proteomes has proven crit-5ical to the field’s advancement. Due to their extraordinary complexity, proteome depth-of-coverage is dependent on advance-ments in technology and related bioinformatics, both of which have made significant advancements in the decade since the last Drosophilasperm proteome was published. Here we provide an updated version of the Drosophila melanogastersperm proteome (DmSP3) using improved separation and detection methods andan updated genome annotation. We identified 2563 proteins,with label-free quantitation (LFQ) for 2125 proteins. Combined with previous versions of the sperm proteome, the DmSP3 contains a total of 3176 proteins. The top 20 most abundant pro-teins contained the structural elements α- and β-tubulins and sperm leucyl-aminopeptidases (S-Laps). Both gene content and protein abundance were significantly reduced on the X chromosome, a finding consistent with prior genomic studies of the X chromosome gene content and evolution. We identified 9 of the 16 Y-linked proteins, including known testis-specific male fertility factors. LFQ measured significant levels for 75/83 ribosomal proteins (RPs) we identified, including a number of core constituents. The role of this unique subset of RPs in sperm is unknown. Surprisingly, our expanded sperm proteome also identified 122 seminal fluid proteins (Sfps), proteins found predominantly in the accessory glands. The possibility of tissue contamination from seminal vesicle or other reproductive tissues was addressed using concentrated salt and detergent treatments. Salt treatment had little effect on sperm proteome composition suggesting only minor contamination during sperm isolation while a significant fraction of Sfps remained associate dwith sperm following detergent treatment suggesting Sfps may arise within, and have additional functions in sperm per se.
2022-10-14 | PXD032033 | Pride
Project description:The ICK (inhibitor cystine knot) defines a large superfamily of polypeptides with high structural stability and functional diversity. Here, we describe a new scorpion venom-derived K+ channel toxin (named λ-MeuKTx-1) with an ICK fold through gene cloning, chemical synthesis, nuclear magnetic resonance spectroscopy, Ca2+ release measurements and electrophysiological recordings. λ-MeuKTx-1 was found to adopt an ICK fold that contains a three-strand anti-parallel β-sheet and a 310-helix. Functionally, this peptide selectively inhibits the Drosophila Shaker K+ channel but is not capable of activating skeletal-type Ca2+ release channels/ryanodine receptors, which is remarkably different from the previously known scorpion venom ICK peptides. The removal of two C-terminal residues of λ-MeuKTx-1 led to the loss of the inhibitory activity on the channel, whereas the C-terminal amidation resulted in the emergence of activity on four mammalian K+ channels accompanied by the loss of activity on the Shaker channel. A combination of structural and pharmacological data allows the recognition of three putative functional sites involved in channel blockade of λ-MeuKTx-1. The presence of a functional dyad in λ-MeuKTx-1 supports functional convergence among scorpion venom peptides with different folds. Furthermore, similarities in precursor organization, exon-intron structure, 3D-fold and function suggest that scorpion venom ICK-type K+ channel inhibitors and Ca2+ release channel activators share a common ancestor and their divergence occurs after speciation between buthidae and non-buthids. The structural and functional characterizations of the first scorpion venom ICK toxin with K+ channel-blocking activity sheds light on functionally divergent and convergent evolution of this conserved scaffold of ancient origin.
| S-EPMC3694633 | biostudies-literature
Project description:BackgroundThe beta-grasp fold (beta-GF), prototyped by ubiquitin (UB), has been recruited for a strikingly diverse range of biochemical functions. These functions include providing a scaffold for different enzymatic active sites (e.g. NUDIX phosphohydrolases) and iron-sulfur clusters, RNA-soluble-ligand and co-factor-binding, sulfur transfer, adaptor functions in signaling, assembly of macromolecular complexes and post-translational protein modification. To understand the basis for the functional versatility of this small fold we undertook a comprehensive sequence-structure analysis of the fold and developed a natural classification for its members.ResultsAs a result we were able to define the core distinguishing features of the fold and numerous elaborations, including several previously unrecognized variants. Systematic analysis of all known interactions of the fold showed that its manifold functional abilities arise primarily from the prominent beta-sheet, which provides an exposed surface for diverse interactions or additionally, by forming open barrel-like structures. We show that in the beta-GF both enzymatic activities and the binding of diverse co-factors (e.g. molybdopterin) have independently evolved on at least three occasions each, and iron-sulfur-cluster-binding on at least two independent occasions. Our analysis identified multiple previously unknown large monophyletic assemblages within the beta-GF, including one which unifies versions found in the fasciclin-1 superfamily, the ribosomal protein L25, the phosphoribosyl AMP cyclohydrolase (HisI) and glutamine synthetase. We also uncovered several new groups of beta-GF domains including a domain found in bacterial flagellar and fimbrial assembly components, and 5 new UB-like domains in the eukaryotes.ConclusionEvolutionary reconstruction indicates that the beta-GF had differentiated into at least 7 distinct lineages by the time of the last universal common ancestor of all extant organisms, encompassing much of the structural diversity observed in extant versions of the fold. The earliest beta-GF members were probably involved in RNA metabolism and subsequently radiated into various functional niches. Most of the structural diversification occurred in the prokaryotes, whereas the eukaryotic phase was mainly marked by a specific expansion of the ubiquitin-like beta-GF members. The eukaryotic UB superfamily diversified into at least 67 distinct families, of which at least 19-20 families were already present in the eukaryotic common ancestor, including several protein and one lipid conjugated forms. Another key aspect of the eukaryotic phase of evolution of the beta-GF was the dramatic increase in domain architectural complexity of proteins related to the expansion of UB-like domains in numerous adaptor roles.
| S-EPMC1949818 | biostudies-literature
Project description:Phytopathogens deliver effector proteins inside host plant cells to promote infection. These proteins can also be sensed by the plant immune system, leading to restriction of pathogen growth. Effector genes can display signatures of positive selection and rapid evolution, presumably a consequence of their co-evolutionary arms race with plants. The molecular mechanisms underlying how effectors evolve to gain new virulence functions and/or evade the plant immune system are poorly understood. Here, we report the crystal structures of the effector domains from two oomycete RXLR proteins, Phytophthora capsici AVR3a11 and Phytophthora infestans PexRD2. Despite sharing <20% sequence identity in their effector domains, they display a conserved core α-helical fold. Bioinformatic analyses suggest that the core fold occurs in ∼44% of annotated Phytophthora RXLR effectors, both as a single domain and in tandem repeats of up to 11 units. Functionally important and polymorphic residues map to the surface of the structures, and PexRD2, but not AVR3a11, oligomerizes in planta. We conclude that the core α-helical fold enables functional adaptation of these fast evolving effectors through (i) insertion/deletions in loop regions between α-helices, (ii) extensions to the N and C termini, (iii) amino acid replacements in surface residues, (iv) tandem domain duplications, and (v) oligomerization. We hypothesize that the molecular stability provided by this core fold, combined with considerable potential for plasticity, underlies the evolution of effectors that maintain their virulence activities while evading recognition by the plant immune system.
| S-EPMC3195559 | biostudies-literature
Project description:The emergence of multicellularity is strongly correlated with the expansion of tyrosine kinases, a conserved family of signaling enzymes that regulates pathways essential for cell-to-cell communication. Although tyrosine kinases have been classified from several model organisms, a molecular-level understanding of tyrosine kinase evolution across all holozoans is currently lacking. Using a hierarchical sequence constraint-based classification of diverse holozoan tyrosine kinases, we construct a new phylogenetic tree that identifies two ancient clades of cytoplasmic and receptor tyrosine kinases separated by the presence of an extended insert segment in the kinase domain connecting the D and E-helices. Present in nearly all receptor tyrosine kinases, this fast-evolving insertion imparts diverse functionalities, such as post-translational modification sites and regulatory interactions. Eph and EGFR receptor tyrosine kinases are two exceptions which lack this insert, each forming an independent lineage characterized by unique functional features. We also identify common constraints shared across multiple tyrosine kinase families which warrant the designation of three new subgroups: Src module (SrcM), insulin receptor kinase-like (IRKL), and fibroblast, platelet-derived, vascular, and growth factor receptors (FPVR). Subgroup-specific constraints reflect shared autoinhibitory interactions involved in kinase conformational regulation. Conservation analyses describe how diverse tyrosine kinase signaling functions arose through the addition of family-specific motifs upon subgroup-specific features and coevolving protein domains. We propose the oldest tyrosine kinases, IRKL, SrcM, and Csk, originated from unicellular premetazoans and were coopted for complex multicellular functions. The increased frequency of oncogenic variants in more recent tyrosine kinases suggests that lineage-specific functionalities are selectively altered in human cancers.
| S-EPMC8662651 | biostudies-literature
Project description:Terpenes are organic compounds and play important roles in plant development and stress response. Terpene synthases (TPSs) are the key enzymes for the biosynthesis of terpenes. For Rosaceae species, terpene composition represents a critical quality attribute, but limited information is available regarding the evolution and expansion occurring in the terpene synthases gene family. Here, we selected eight Rosaceae species with sequenced and annotated genomes for the identification of TPSs, including three Prunoideae, three Maloideae, and two Rosoideae species. Our data showed that the TPS gene family in the Rosaceae species displayed a diversity of family numbers and functions among different subfamilies. Lineage and species-specific expansion of the TPSs accompanied by frequent domain loss was widely observed within different TPS clades, which might have contributed to speciation or environmental adaptation in Rosaceae. In contrast to Maloideae and Rosoideae species, Prunoideae species owned less TPSs, with the evolution of Prunoideae species, TPSs were expanded in modern peach. Both tandem and segmental duplication significantly contributed to TPSs expansion. Ka/Ks calculations revealed that TPSs genes mainly evolved under purifying selection except for several pairs, where the divergent time indicated TPS-e clade was diverged relatively anciently. Gene function classification of TPSs further demonstrated the function diversity among clades and species. Moreover, based on already published RNA-Seq data from NCBI, the expression of most TPSs in Malus domestica, Prunus persica, and Fragaria vesca displayed tissue specificity and distinct expression patterns either in tissues or expression abundance between species and TPS clades. Certain putative TPS-like proteins lacking both domains were detected to be highly expressed, indicating the underlying functional or regulatory potentials. The result provided insight into the TPS family evolution and genetic information that would help to improve Rosaceae species quality.
| S-EPMC8953233 | biostudies-literature
Project description:Sequences of fast-folding model proteins (48 residues long on a cubic lattice) were generated by an evolution-like selection toward fast folding. We find that fast-folding proteins exhibit a specific folding mechanism in which all transition state conformations share a smaller subset of common contacts (folding nucleus). Acceleration of folding was accompanied by dramatic strengthening of interactions in the folding nucleus whereas average energy of nonnucleus interactions remained largely unchanged. Furthermore, the residues involved in the nucleus are the most conserved ones within families of evolved sequences. Our results imply that for each protein structure there is a small number of conserved positions that are key determinants of fast folding into that structure. This conjecture was tested on two protein superfamilies: the first having the classical monophosphate binding fold (CMBF; 98 families) and the second having type-III repeat fold (47 families). For each superfamily, we discovered a few positions that exhibit very strong and statistically significant "conservatism of conservatism"-amino acids in those positions are conserved within every family whereas the actual types of amino acids varied from family to family. Those amino acids are in spatial contact with each other. The experimental data of Serrano and coworkers [Lopez-Hernandez, E. & Serrano, L. (1996) Fold. Des. (London) 1, 43-55]. for one of the proteins of the CMBF superfamily (CheY) show that residues identified this way indeed belong to the folding nucleus. Further analysis revealed deep connections between nucleation in CMBF proteins and their function.
| S-EPMC20198 | biostudies-literature
Project description:The mammalian central nervous system (CNS) exhibits a remarkable ability to process, store, and transfer information. Key to these activities is the use of highly regulated and unique patterns of calcium signals encoded by calcium channels and decoded by families of specific calcium-sensing proteins. The largest family of eukaryotic calcium sensors is those related to the small EF-hand containing protein calmodulin (CaM). In order to maximize the usefulness of calcium as a signaling species and to permit the evolution and fine tuning of the mammalian CNS, families of related proteins have arisen that exhibit characteristic calcium binding properties and tissue-, cellular-, and sub-cellular distribution profiles. The Calcium Binding Proteins (CaBPs) represent one such family of vertebrate specific CaM like proteins that have emerged in recent years as important regulators of essential neuronal target proteins. Bioinformatic analyses indicate that the CaBPs consist of two subfamilies and that the ancestral members of these are CaBP1 and CaBP8. The CaBPs have distinct intracellular localizations based on different targeting mechanisms including a novel type-II transmembrane domain in CaBPs 7 and 8 (otherwise known as calneuron II and calneuron I, respectively). Recent work has led to the identification of new target interactions and possible functions for the CaBPs suggesting that they have multiple physiological roles with relevance for the normal functioning of the CNS.
| S-EPMC3284769 | biostudies-literature
Project description:Globins are small heme-proteins that reversibly bind oxygen. Their most prominent roles in vertebrates are the transport and storage of O2 for oxidative energy metabolism, but recent research has suggested alternative, non-respiratory globin functions. In the species-rich and ecologically highly diverse taxon of arthropods, the copper-containing hemocyanin is considered the main respiratory protein. However, recent studies have suggested the presence of globin genes and their proteins in arthropod taxa, including model species like Drosophila. To systematically assess the taxonomic distribution, evolution and diversity of globins in arthropods, we systematically searched transcriptome and genome sequence data and found a conserved, widespread occurrence of three globin classes in arthropods: hemoglobin-like (HbL), globin X (GbX), and globin X-like (GbXL) protein lineages. These globin types were previously identified in protostome and deuterostome animals including vertebrates, suggesting their early ancestry in Metazoa. The HbL genes show multiple, lineage-specific gene duplications in all major arthropod clades. Some HbL genes (e.g., Glob2 and 3 of Drosophila) display particularly fast substitution rates, possibly indicating the evolution of novel functions, e.g., in spermatogenesis. In contrast, arthropod GbX and GbXL globin genes show high evolutionary stability: GbXL is represented by a single-copy gene in all arthropod groups except Brachycera, and representatives of the GbX clade are present in all examined taxa except holometabolan insects. GbX and GbXL both show a brain-specific expression. Most arthropod GbX and GbXL proteins, but also some HbL variants, include sequence motifs indicative of potential N-terminal acylation (i.e., N-myristoylation, 3C-palmitoylation). All arthropods except for the brachyceran Diptera harbor at least one such potentially acylated globin copy, confirming the hypothesis of an essential, conserved globin function associated with the cell membrane. In contrast to other animals, the fourth ancient globin lineage, represented by neuroglobin, appears to be absent in arthropods, and the putative arthropod orthologs of the fifth metazoan globin lineage, androglobin, lack a recognizable globin domain. Thus, the remarkable evolutionary stability of some globin variants is contrasted by occasional dynamic gene multiplication or even loss of otherwise strongly conserved globin lineages in arthropod phylogeny.
| S-EPMC7457136 | biostudies-literature