Virus and eukaryote fusogen superfamilies.
Ontology highlight
ABSTRACT:
SUBMITTER: Vance TDR
PROVIDER: S-EPMC7336913 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
Virus and eukaryote fusogen superfamilies.
Vance Tyler D R TDR Lee Jeffrey E JE
Current biology : CB 20200701 13
Similar Datasets
Project description:Superfamily classifications are based variably on similarity of sequences, global folds, local structures, or functions. We have examined the possibility of defining superfamilies purely from the viewpoint of the global fold/function relationship. For this purpose, we first classified protein domains according to the beta-sheet topology. We then introduced the concept of kinship relations among the classified beta-sheet topology by assuming that the major elementary event leading to creation of a new beta-sheet topology is either an addition or deletion of one beta-strand at the edge of an existing beta-sheet during the molecular evolution. Based on this kinship relation, a network of protein domains was constructed so that the distance between a pair of domains represents the number of evolutionary events that lead one from the other domain. We then mapped on it all known domains with a specific core chemical function (here taken, as an example, that involving ATP or its analogs). Careful analyses revealed that the domains are found distributed on the network as >20 mutually disjointed clusters. The proteins in each cluster are defined to form a fold-based superfamily. The results indicate that >20 ATP-binding protein superfamilies have been invented independently in the process of molecular evolution, and the conservative evolutionary diffusion of global folds and functions is the origin of the relationship between them.
| S-EPMC2366925 | biostudies-literature
Project description:Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research tools, drug leads and even therapeutics, and has resulted in a concerted and increasing drive to identify and characterise new conotoxins. Conotoxins are translated from mRNA as peptide precursors, and cDNA sequencing is now the primary method for identification of new conotoxin sequences. As a result, gene superfamily, a classification based on precursor signal peptide identity, has become the most convenient method of conotoxin classification. Here we review each of the described conotoxin gene superfamilies, with a focus on the structural and functional diversity present in each. This review is intended to serve as a practical guide to conotoxin superfamilies and to facilitate interpretation of the increasing number of conotoxin precursor sequences being identified by targeted-cDNA sequencing and more recently high-throughput transcriptome sequencing.
| S-EPMC4278219 | biostudies-literature
Project description:Viral fusogens merge viral and cell membranes during cell penetration. Their ectodomains drive fusion by undergoing large-scale refolding, but little is known about the functionally important regions located within or near the membrane. Here we report the crystal structure of full-length glycoprotein B (gB), the fusogen from herpes simplex virus, complemented by electron spin resonance measurements. The membrane-proximal (MPR), transmembrane (TMD), and cytoplasmic (CTD) domains form a uniquely folded trimeric pedestal beneath the ectodomain, which balances dynamic flexibility with extensive, stabilizing membrane interactions. The postfusion conformation of the ectodomain suggests that the CTD likewise adopted the postfusion form. However, hyperfusogenic mutations, which destabilize the prefusion state of gB, target key interfaces and structural motifs that reinforce the observed CTD structure. Thus, a similar CTD structure must stabilize gB in its prefusion state. Our data suggest a model for how this dynamic, membrane-dependent 'clamp' controls the fusogenic refolding of gB.
| S-EPMC5942590 | biostudies-literature
Project description:Membrane fusion during the entry of herpesviruses is carried out by the viral fusogen gB that is activated by its partner protein gH in some manner. The fusogenic activity of gB is controlled by its cytoplasmic (or intraviral) domain (gBCTD) and, according to the current model, the gBCTD is a trimeric, inhibitory clamp that restrains gB in the prefusion conformation. But how the gBCTD clamp is released by gH is unclear. Here, we identified two new regulatory elements within gB and gH from the prototypical herpes simplex virus 1: a surface pocket within the gBCTD and residue V831 within the gH cytoplasmic tail. Mutagenesis and structural modeling suggest that gH V831 interacts with the gB pocket. The gB pocket is located above the interface between adjacent protomers, and we hypothesize that insertion of the gH V831 wedge into the pocket serves to push the protomers apart, which releases the inhibitory clamp. In this manner, gH activates the fusogenic activity of gB. Both gB and gH are conserved across all herpesviruses, and this activation mechanism could be used by other gB homologs. Our proposed mechanism emphasizes a central role for the cytoplasmic regions in regulating the activity of a viral fusogen.
| S-EPMC9275723 | biostudies-literature
Project description:Phylogenomic study of Sciaroidea
| PRJNA797684 | ENA
Project description:Whilst ∼93% of domain superfamilies appear to be relatively structurally and functionally conserved based on the available data from the CATH-Gene3D domain classification resource, the remainder are much more diverse. In this review, we consider how domains in some of the most ubiquitous and promiscuous superfamilies have evolved, in particular the plasticity in their functional sites and surfaces which expands the repertoire of molecules they interact with and actions performed on them. To what extent can we identify a core function for these superfamilies which would allow us to develop a 'domain grammar of function' whereby a protein's biological role can be proposed from its constituent domains? Clearly the first step is to understand the extent to which these components vary and how changes in their molecular make-up modifies function.
| S-EPMC4686048 | biostudies-literature
Project description:Complex bacterial glycoconjugates are essential for bacterial survival, and drive interactions between pathogens and symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane interface by phosphoglycosyl transferases (PGTs), which catalyze the transfer of a phosphosugar from a soluble uridine diphospho-sugar (UDP-sugar) substrate to a membrane-bound polyprenol-phosphate (Pren-P). Two distinct superfamilies of PGT enzymes, denoted as polytopic and monotopic, carry out this reaction but show striking differences in structure and mechanism. With the goal of creating non-hydrolyzable mimics (UBP-sugars) of the UDP-sugar substrates as chemical probes to interrogate critical aspects of these essential enzymes, we designed and synthesized a series of uridine bisphosphonates (UBPs), wherein the diphosphate bridging oxygen of the UDP and UDP-sugar is replaced by a substituted methylene group (CXY; X/Y = F/F, Cl/Cl, (S)-H/F, (R)-H/F, H/H, CH3/CH3). These compounds, which incorporated as the conjugating sugar an N-acetylglucosamine (GlcNAc) substituent at the β-phosphonate, were evaluated as inhibitors of a representative polytopic PGT (WecA from Thermotoga maritima) and a monotopic PGT (PglC from Campylobacter jejuni). Although CHF-BP most closely mimics pyrophosphate with respect to its acid/base properties, the less basic CF2-BP conjugate most strongly inhibited PglC, whereas the more basic CH2-BP analogue was the strongest inhibitor of WecA. These surprising differences indicate different modes of ligand binding for the different PGT superfamilies implicating a modified P-O- interaction with the structural Mg2+, consistent with their catalytic divergence. Furthermore, at least for the monoPGT superfamily example, this was not the sole determinant of ligand binding: the two diastereomeric CHF-BP conjugates, which feature a chiral center at the Pα-CHF-Pβ carbon, exhibited strikingly different binding affinities and the inclusion of GlcNAc with the native α-anomer configuration significantly improved binding affinity. UBP-sugars are a valuable tool for elucidating the structures and mechanisms of the distinct PGT superfamilies and offer a promising scaffold to develop novel antibiotic agents for the exclusively prokaryotic monoPGT superfamily.
| S-EPMC10541605 | biostudies-literature
Project description:We present, to our knowledge, the first quantitative analysis of functional site diversity in homologous domain superfamilies. Different types of functional sites are considered separately. Our results show that most diverse superfamilies are very plastic in terms of the spatial location of their functional sites. This is especially true for protein-protein interfaces. In contrast, we confirm that catalytic sites typically occupy only a very small number of topological locations. Small-ligand binding sites are more diverse than expected, although in a more limited manner than protein-protein interfaces. In spite of the observed diversity, our results also confirm the previously reported preferential location of functional sites. We identify a subset of homologous domain superfamilies where diversity is particularly extreme, and discuss possible reasons for such plasticity, i.e. structural diversity. Our results do not contradict previous reports of preferential co-location of sites among homologues, but rather point at the importance of not ignoring other sites, especially in large and diverse superfamilies. Data on sites exploited by different relatives, within each well annotated domain superfamily, has been made accessible from the CATH website in order to highlight versatile superfamilies or superfamilies with highly preferential sites. This information is valuable for system biology and knowledge of any constraints on protein interactions could help in understanding the dynamic control of networks in which these proteins participate. The novelty of our work lies in the comprehensive nature of the analysis - we have used a significantly larger dataset than previous studies - and the fact that in many superfamilies we show that different parts of the domain surface are exploited by different relatives for ligand/protein interactions, particularly in superfamilies which are diverse in sequence and structure, an observation not previously reported on such a large scale. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.
| S-EPMC3787744 | biostudies-literature
Project description:Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane interface by phosphoglycosyl transferases (PGTs), which catalyze the transfer of a phosphosugar from a soluble uridine diphosphosugar (UDP-sugar) substrate to a membrane-bound polyprenol-phosphate (Pren-P). The two distinct superfamilies of PGT enzymes (polytopic and monotopic) show striking differences in their structure and mechanism. We designed and synthesized a series of uridine bisphosphonates (UBPs), wherein the diphosphate of the UDP and UDP-sugar is replaced by a substituted methylene bisphosphonate (CXY-BPs; X/Y = F/F, Cl/Cl, (S)-H/F, (R)-H/F, H/H, CH3/CH3). UBPs and UBPs incorporating an N-acetylglucosamine (GlcNAc) substituent at the β-phosphonate were evaluated as inhibitors of a polytopic PGT (WecA from Thermotoga maritima) and a monotopic PGT (PglC from Campylobacter jejuni). Although CHF-BP most closely mimics diphosphate with respect to its acid/base properties, the less basic CF2-BP conjugate more strongly inhibited PglC, whereas the more basic CH2-BP analogue was the strongest inhibitor of WecA. These surprising differences indicate different modes of ligand binding for the different PGT superfamilies, implicating a modified P-O- interaction with the structural Mg2+. For the monoPGT enzyme, the two diastereomeric CHF-BP conjugates, which feature a chiral center at the Pα-CHF-Pβ carbon, also exhibited strikingly different binding affinities and the inclusion of GlcNAc with the native α-anomer configuration significantly improved binding affinity. UBP-sugars are thus revealed as informative new mechanistic probes of PGTs that may aid development of novel antibiotic agents for the exclusively prokaryotic monoPGT superfamily.
| S-EPMC10922802 | biostudies-literature