Publications & Products

Research products from students and faculty in the Center for Biological Data Science. Student co-authors are indicated with (§) for undergraduates and (‡) for graduates; postdocs are indicaed by (*).

Wang, H., G.E. Kellogg, P. Xu, and Y. Zhang (2018) Exploring the binding mechanisms of diaminopimelic acid analogs to meso-diaminopimelate dehydrogenase by molecular modeling. Journal of Molecular Graphics & Modelling 83:100-111.

https://doi.org/10.1016/j.jmgm.2018.05.011

Abstract

Meso-Diaminopimelic acid (meso-2,6-diamino-heptanedioic acid, DAP) is an important component of the cell wall of many bacteria. Meso-diaminopimelate dehydrogenase (m-Ddh) is a critical enzyme in the process of converting tetrahydrodipicolinate to DAP. Here, we are proposing that DAP analogs targeting m-Ddh may be considered as potential antibiotics. Four DAP analogs without significant structural change from DAP have been obtained and their inhibitory potencies against m-Ddh from the P. gingivalis strain W83 show significant differences from that of DAP. However, their inhibitory mechanisms as for how simple structural change influences the inhibitory potency remain unknown. Therefore, we employed molecular modeling methods to obtain insight into the inhibitory mechanisms of DAP and analogs with m-Ddh. The predicted binding mode of DAP was highly consistent with the experimental structural data and disclosed the important roles played by the binding pocket residues. According to our predictions, the isoxazoline ring of compounds 1 and 2 and the double bonds in compounds 3 and 4 had distinct influences on these compounds' binding to m-Ddh. This enriched understanding of the inhibitory mechanisms of DAP and these four analogs to m-Ddh has provided new and relevant information for future rational development of potent inhibitors targeting m-Ddh.

Zhu, B.*, L.C. Macleod, T. Kitten, and P. Xu (2018) Streptococcus sanguinis biofilm formation & interaction with oral pathogens. Future Microbiology 13:915-932.

https://doi.org/10.2217/fmb-2018-0043

Abstract

Caries and periodontitis are the two most common human dental diseases and are caused by dysbiosis of oral flora. Although commensal microorganisms have been demonstrated to protect against pathogens and promote oral health, most previous studies have addressed pathogenesis rather than commensalism. Streptococcus sanguinis is a commensal bacterium that is abundant in the oral biofilm and whose presence is correlated with health. Here, we focus on the mechanism of biofilm formation in S. sanguinis and the interaction of S. sanguinis with caries- and periodontitis-associated pathogens. In addition, since S. sanguinis is well known as a cause of infective endocarditis, we discuss the relationship between S. sanguinis biofilm formation and its pathogenicity in endocarditis.

Zhu, B.*, L. Song, X. Kong*, L.C. Macleod, P. Xu (2018) A novel regulator modulates glucan production, cell aggregation and biofilm formation in Streptococcus sanguinis SK36. Frontiers in Microbiology 9:1154.

https://doi.org/10.3389/fmicb.2018.01154

Abstract

Streptococcus sanguinis is an early colonizer of tooth surfaces and a key player in plaque biofilm development. However, the mechanism of biofilm formation of S. sanguinis is still unclear. Here, we showed that deletion of a transcription factor, brpL, promotes cell aggregation and biofilm formation in S. sanguinis SK36. Glucan, a polysaccharide synthesized from sucrose, was over-produced and aggregated in the biofilm of ΔbrpL, which was necessary for better biofilm formation ability of ΔbrpL. Quantitative RT-PCR demonstrated that gtfP was significantly up-regulated in ΔbrpL, which increased the productions of water-insoluble and water-soluble glucans. The ΔbrpLΔgtfP double mutant decreased biofilm formation ability of ΔbrpL to a level similar like that of ΔgtfP. Interestingly, the biofilm of ΔbrpL had an increased tolerance to ampicillin treatment, which might be due to better biofilm formation ability through the mechanisms of cellular and glucan aggregation. RNA sequencing and quantitative RT-PCR revealed the modulation of a group of genes in ΔbrpL was mediated by activating the expression of ciaR, another gtfP-related biofilm formation regulator. Double deletion of brpL and ciaR decreased biofilm formation ability to the phenotype of a ΔciaRmutant. Additionally, RNA sequencing elucidated a broad range of genes, related to carbohydrate metabolism and uptake, were activated in ΔbrpL. SSA_0222, a gene involved in the phosphotransferase system, was dramatically up-regulated in ΔbrpL and essential for S. sanguinissurvival under our experimental conditions. In summary, brpL modulates glucan production, cell aggregation and biofilm formation by regulating the expression of ciaR in S. sanguinis SK36.

El-Rami, F.‡, X. Kong*, H. Parikh, B. Zhu*, V. Stone*, T. Kitten, and P. Xu (2018) Analysis of essential gene dynamics under antibiotic stress in Streptococcus sanguinis. Microbiology 164(2):173-185.

https://doi.org/10.1099/mic.0.000595

Abstract

The paradoxical response of Streptococcus sanguinis to drugs prescribed for dental and clinical practices has complicated treatment guidelines and raised the need for further investigation. We conducted a high throughput study on concomitant transcriptome and proteome dynamics in a time course to assess S. sanguinis behaviour under a sub-inhibitory concentration of ampicillin. Temporal changes at the transcriptome and proteome level were monitored to cover essential genes and proteins over a physiological map of intricate pathways. Our findings revealed that translation was the functional category in S. sanguinis that was most enriched in essential proteins. Moreover, essential proteins in this category demonstrated the greatest conservation across 2774 bacterial proteomes, in comparison to other essential functional categories like cell wall biosynthesis and energy production. In comparison to non-essential proteins, essential proteins were less likely to contain 'degradation-prone' amino acids at their N-terminal position, suggesting a longer half-life. Despite the ampicillin-induced stress, the transcriptional up-regulation of amino acid-tRNA synthetases and proteomic elevation of amino acid biosynthesis enzymes favoured the enriched components of essential proteins revealing 'proteomic signatures' that can be used to bridge the genotype-phenotype gap of S. sanguinis under ampicillin stress. Furthermore, we identified a significant correlation between the levels of mRNA and protein for essential genes and detected essential protein-enriched pathways differentially regulated through a persistent stress response pattern at late time points. We propose that the current findings will help characterize a bacterial model to study the dynamics of essential genes and proteins under clinically relevant stress conditions.

Rosenberg, M.S. (2018) New record and range extension of the fiddler crab Uca princeps (Smith, 1870) (Brachyura, Ocypodidae) from California, USA. Journal of Crustacean Biology

https://doi.org/10.1093/jcbiol/ruy071

Abstract

The fiddler crab Uca princeps (Smith, 1870) has previously been recorded along the Pacific coast of the Americas from Peru to Mexico. Here we extend its range into the United States, based on photographs posted on the iNaturalist website.

Rodionova, I.A., N. Goodacre‡, J. Do, A. Hosseinnia, M. Babu, P. Uetz, and M.H. Saier, Jr. (2018) The uridylyltransferase, GlnD, and tRNA modification GTPase, MnmE allosterically control Escherichia coli folylpoly-γ-glutamate synthase, FolC. Journal of Biological Chemistry

https://doi.org/10.1074/jbc.RA118.004425

Abstract

Folate derivatives are important cofactors for enzymes in several metabolic processes. Folate-related inhibition and resistance mechanisms in bacteria are potential targets for antimicrobial therapies and therefore a significant focus of current research. Here, we report that the activity of Escherichia coli poly-γ-glutamyl tetrahydrofolate/dihydrofolate synthase (FolC) is regulated by the glutamate/glutamine-sensing uridylyltransferase (GlnD), the THF-dependent tRNA modification enzyme (MnmE) and the UDP-glucose dehydrogenase (Ugd) as shown by direct in vitro protein-protein interactions.

Using kinetics analyses, we observed that GlnD, Ugd, and MnmE activate FolC many fold by decreasing the Khalf of FolC for its substrate, L-glutamate. Moreover, FolC inhibited the GTPase activity of MnmE at low GTP concentrations. The growth phenotypes associated with these proteins are discussed. These results, obtained using direct in vitro enzyme assays, reveal unanticipated networks of allosteric regulatory interactions in the folate pathway in E. coli and indicate regulation of polyglutamylated tetrahydrofolate biosynthesis by the availability of nitrogen sources, signaled by the glutamine-sensing GlnD protein.

Goodacre, N.‡, P. Devkota, E. Bae, S. Wuchty, and P. Uetz (2018) Protein-protein interactions of human viruses. Seminars in Cell & Developmental Biology

https://doi.org/10.1016/j.semcdb.2018.07.018

Abstract

Viruses infect their human hosts by a series of interactions between viral and host proteins, indicating that detailed knowledge of such virus-host interaction interfaces are critical for our understanding of viral infection mechanisms, disease etiology and the development of new drugs. In this review, we primarily survey human host-virus interaction data that are available from public databases following the standardized PSI-MS format. Notably, available host-virus protein interaction information is strongly biased toward a small number of virus families including herpesviridae, papillomaviridae, orthomyxoviridae and retroviridae. While we explore the reliability and relevance of these protein interactions we also survey the current knowledge about viruses functional and topological targets. Furthermore, we assess emerging frontiers of host-virus protein interaction research, focusing on protein interaction interfaces of hosts that are infected by different viruses and viruses that infect multiple hosts. Finally, we cover the current status of research that investigates the relationships of virus-targeted host proteins to other comorbidities as well as the influence of host-virus protein interactions on human metabolism.

Elhai, J., and I. Khudyakov (2018) Ancient association of cyanobacterial multicellularity with the regulator HetR and an RGSGR pentapeptide‐containing protein (PatX). Molecular Microbiology

https://doi.org/10.1111/mmi.14003

Abstract

One simple model to explain biological pattern postulates the existence of a stationary regulator of differentiation that positively affects its own expression, coupled with a diffusible suppressor of differentiation that inhibits the regulator's expression. The first has been identified in the filamentous, heterocyst-forming cyanobacterium, Anabaena PCC 7120 as the transcriptional regulator, HetR, and the second as the small protein, PatS, which contains a critical RGSGR motif that binds to HetR. HetR is present in almost all filamentous cyanobacteria, but only a subset of heterocyst-forming strains carry proteins similar to PatS. We identified a third protein, PatX that also carries the RGSGR motif and is coextensive with HetR. Amino acid sequences of PatX contain two conserved regions: the RGSGR motif and a hydrophobic N‐terminus. Within 69 nt upstream from all instances of the gene is a DIF1 motif correlated in Anabaena with promoter induction in developing heterocysts, preceded in heterocyst-forming strains by an apparent NtcA-binding site, associated with regulation by nitrogen-status. Consistent with a role in the simple model, PatX is expressed dependent on HetR and acts to inhibit differentiation. The acquisition of the PatX/HetR pair preceded the appearance of both PatS and heterocysts, dating back to the beginnings of multicellularity.

Uetz, P., J. Mehla, K. Sinner, F. Oesterheld, K. Richter, D. Schubert, and C. Urbanke (2018) Protein-protein interactions. Bioanalytics, F. Lottspeich, ed. Pp. 381-417.

https://www.wiley.com/en-us/Bioanalytics%3A+Analytical+Methods+and+Concepts+in+Biochemistry+and+Molecular+Biology-p-9783527694464

Abstract

None

Wuchty S., S.A. Mueller, J.H. Caufield‡, R. Häuser, P. Aloy, S. Kalkhof, and P. Uetz (2018) Proteome data improves protein function prediction in the interactome of H. pylori. Molecular & Cellular Proteomics 17:961-973.

http://doi.org/10.1074/mcp.RA117.000474

Abstract

Helicobacter pylori is a common pathogen that is estimated to infect half of the human population, causing several diseases such as duodenal ulcer. Despite one of the first pathogens to be sequenced, its proteome remains poorly characterised as about one third of its proteins have no functional annotation. Here, we integrate and analyze known protein interactions with proteomic and genomic data from different sources. We find that proteins with similar abundances tend to interact. Such an observation is accompanied by a trend of interactions to appear between proteins of similar functions, although some show marked cross-talk to others. Protein function prediction with protein interactions is significantly improved when interactions from other bacteria are included in our network, allowing us to obtain putative functions of more than 300 poorly or previously uncharacterized proteins. Proteins that are critical for the topological controllability of the underlying network are significantly enriched with genes that are up-regulated in the spiral compared to the coccoid form of H. pylori. Determining their evolutionary conservation, we present evidence for 80 protein complexes to be identical in composition with their counterparts in E. coli while 85 are partially conserved but 120 complexes are completely absent. Furthermore, we determine network clusters that coincide with related functions gene essentiality, genetic context, cellular localization, and gene expression in different cellular states.

Uetz, P., and A. Stylianou‡ (2018) The original descriptions of reptiles and their subspecies Zootaxa 4375:257-264.

http://dx.doi.org/10.11646/zootaxa.4375.2.5

Abstract

By August 2017 an estimated 13,047 species and subspecies of extant reptiles have been described by a total of 6,454 papers and books which are listed in a supplementary file. For 1,052 species a total of 2,452 subspecies (excluding nominate subspecies) had been described by 2017, down from 1,295 species and 4,411 subspecies in 2009, due to the elevation of many subspecies to species. Here we summarize the history of these taxon description beginning with Linnaeus in 1758. While it took 80 years to reach the first 1,000 species in 1838, new species and subspecies descriptions since then have been added at a roughly constant rate of 1000 new taxa every 12-17 years. The only exception were the decades during World Wars I and II and the beginning of this millennium when the rate of descriptions increased to now about 7 years for the last 1,000 taxa. The top 101 most productive herpetologists (in terms of “taxon output”) have described more than 8,000 species and subspecies, amounting to over 60% of all currently valid taxa. More than 90% of all species were described in either English (68.2%), German (12.7%) or French (9.3%).

Mehla J.*, J.H. Caufield‡, and P. Uetz (2018) Making the right choice: Critical parameters of the Y2H systems Two-Hybrid Systems. Methods in Molecular Biology, Oñate-Sánchez, L., ed. 1794:17-28.

https://doi.org/10.1007/978-1-4939-7871-7_2

Abstract

Two-hybrid methods remain among the most preferred choices for detecting protein–protein interactions (PPIs) and much of the PPI data in databases have been produced using yeast two-hybrid (Y2H) screens. The Y2H methods are extensively used to detect PPIs because of their scalability and accessibility. Several variants of Y2H methods have been developed and used by different research groups, increasing the accessibility of these methods and their applications in detecting different types of PPIs. However, the availability of variations on the same core methodology emphasizes the need to have a systematic comparison of available Y2H methods in the context of their applicability, coverage and efficiency. In this chapter, we discuss the key parameters of Y2H methods, namely proteins of interest, vectors, libraries, screening strategies, data analysis, and provide a flowchart that should help to decide which Y2H strategy is most appropriate for a protein interaction screen.