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Advances in Proteomic Research for the Characterization of Bioactive Molecules

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2017) | Viewed by 62446

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Dr. Sebastien Dutertre

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Institut des Biomolécules Max Mousseron, UMR 5247, Université Montpellier, CNRS, Place Eugène Bataillon, 34095 Montpellier CEDEX 5, France
Interests: venoms; conotoxins; peptides; proteomics; transcriptomics; drug discovery
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Special Issue Information

Dear Colleagues,

Bioactive molecules produced by some plants, microbes, and animals constitute a large reservoir of natural products with potential as new therapeutics, agrochemicals and cosmetics. Whereas small molecules (<500 Da) represent the majority of characterized biologically-active components, larger molecules, such as neuropeptides, hormones, toxins, and enzymes, are also of interest. However, until recently, the amount of starting material required for characterization limited the number of species that could be investigated. With the advent of more sensitive mass spectrometry instruments, coupled to transcriptomics and bioinformatics tools, researchers can, nowadays, interrogate virtually any species, from the smallest to the rarest. In addition, a deeper understanding of the biology/ecology of these species, as well as their evolution, can be inferred from such integrated approach, while providing a framework for the rational discovery of novel biomolecules. This Special Issue will contain articles describing new advances in proteomic research for the characterization of such bioactive molecules.

Topics of this Special Issue include, but are not limited to:

Transcriptomics/Proteomics
Peptides and peptidomimetic drugs
Glycopeptides
Imaging and analytical techniques
Peptide-based proteomics databases
New Bioinformatics approaches for the integration of proteomic and transcriptomic datasets
Sample preparation for two-dimensional electrophoresis
Sample preparation for protein mass spectrometry
Enrichment for sub-proteomes
Organelle proteomics
Clinical applications of proteomics, such as biomarker discovery
Proteomics of non-model organisms

Prof. Dutertre Sebastien
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

Biomolecules
peptides
hormones
enzymes
polyamines
alkaloids
proteomics
transcriptomics

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Published Papers (10 papers)

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Research

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22 pages, 3571 KiB

Open AccessArticle

Time Dependent Pathway Activation of Signalling Cascades in Rat Organs after Short-Term Hyperoxia

by Jochen Hinkelbein, Stefan Braunecker, Matthias Danz, Lennert Böhm and Andreas Hohn

Int. J. Mol. Sci. 2018, 19(7), 1960; https://doi.org/10.3390/ijms19071960 - 4 Jul 2018

Cited by 6 | Viewed by 3643

Abstract

Administration of oxygen is one of the most common interventions in medicine. Previous research showed that differential regulated proteins could be linked to hyperoxia-associated signaling cascades in different tissues. However, it still remains unclear which signaling pathways are activated by hyperoxia. The present study analyses hyperoxia-induced protein alterations in lung, brain, and kidney tissue using a proteomic and bioinformatic approach. Pooled data of 36 Wistar rats exposed to hyperoxia were used. To identify possible hyperoxia biomarkers, and to evaluate the relationship between protein alterations in hyperoxia affected organs and blood, proteomics data from brain, lung, and kidney were analyzed. Functional network analyses (IPA^®, PathwaysStudio^®, and GENEmania^®) in combination with hierarchical cluster analysis (Perseus^®) was used to identify relevant pathways and key proteins. Data of 54 2D-gels with more than 2500 significantly regulated spots per gel were collected. Thirty-eight differentially expressed proteins were identified and consecutively analyzed by bioinformatic methods. Most differences between hyperoxia and normoxia (21 proteins up-regulated, 17 proteins down-regulated) were found immediately after hyperoxia (15 protein spots), followed by day 3 (13 spots), and day 7 (10 spots). A highly significant association with inflammation and the inflammatory response was found. Cell proliferation, oxidative stress, apoptosis and cell death as well as cellular functions were revealed to be affected. Three hours of hyperoxia resulted in significant alterations of protein expression in different organs (brain, lung, kidney) up to seven days after exposure. Further studies are required to interpret the relevance of protein alterations in signaling cascades during/after hyperoxia. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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19 pages, 3287 KiB

Open AccessArticle

Biochemical and MALDI-TOF Mass Spectrometric Characterization of a Novel Native and Recombinant Cystine Knot Miniprotein from Solanum tuberosum subsp. andigenum cv. Churqueña

by Juliana Cotabarren, Mariana Edith Tellechea, Sebastián Martín Tanco, Julia Lorenzo, Javier Garcia-Pardo, Francesc Xavier Avilés and Walter David Obregón

Int. J. Mol. Sci. 2018, 19(3), 678; https://doi.org/10.3390/ijms19030678 - 28 Feb 2018

Cited by 7 | Viewed by 4298

Abstract

Cystine-knot miniproteins (CKMPs) are an intriguing group of cysteine-rich molecules that combine the characteristics of proteins and peptides. Typically, CKMPs are fewer than 50 residues in length and share a characteristic knotted scaffold characterized by the presence of three intramolecular disulfide bonds that form the singular knotted structure. The knot scaffold confers on these proteins remarkable chemical, thermal, and proteolytic stability. Recently, CKMPs have emerged as a novel class of natural molecules with interesting pharmacological properties. In the present work, a novel cystine-knot metallocarboxypeptidase inhibitor (chuPCI) was isolated from tubers of Solanum tuberosum, subsp. andigenum cv. Churqueña. Our results demonstrated that chuPCI is a member of the A/B-type family of metallocarboxypeptidases inhibitors. chuPCI was expressed and characterized by a combination of biochemical and mass spectrometric techniques. Direct comparison of the MALDI-TOF mass spectra for the native and recombinant molecules allowed us to confirm the presence of four different forms of chuPCI in the tubers. The majority of such forms have a molecular weight of 4309 Da and contain a cyclized Gln in the N-terminus. The other three forms are derived from N-terminal and/or C-terminal proteolytic cleavages. Taken together, our results contribute to increase the current repertoire of natural CKMPs. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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16 pages, 2934 KiB

Open AccessArticle

Comparative Membrane-Associated Proteomics of Three Different Immune Reactions in Potato

by Dharani Dhar Burra, Marit Lenman, Fredrik Levander, Svante Resjö and Erik Andreasson

Int. J. Mol. Sci. 2018, 19(2), 538; https://doi.org/10.3390/ijms19020538 - 10 Feb 2018

Cited by 14 | Viewed by 6595

Abstract

Plants have evolved different types of immune reactions but large-scale proteomics about these processes are lacking, especially in the case of agriculturally important crop pathosystems. We have established a system for investigating PAMP-triggered immunity (PTI) and two different effector-triggered immunity (ETI; triggered by Avr2 or IpiO) responses in potato. The ETI responses are triggered by molecules from the agriculturally important Phytophthora infestans interaction. To perform large-scale membrane protein-based comparison of these responses, we established a method to extract proteins from subcellular compartments in leaves. In the membrane fractions that were subjected to quantitative proteomics analysis, we found that most proteins regulated during PTI were also regulated in the same way in ETI. Proteins related to photosynthesis had lower abundance, while proteins related to oxidative and biotic stress, as well as those related to general antimicrobial defense and cell wall degradation, were found to be higher in abundance. On the other hand, we identified a few proteins—for instance, an ABC transporter-like protein—that were only found in the PTI reaction. Furthermore, we also identified proteins that were regulated only in ETI interactions. These included proteins related to GTP binding and heterotrimeric G-protein signaling, as well as those related to phospholipase signaling. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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11 pages, 1829 KiB

Open AccessCommunication

Preservation Method and Phosphate Buffered Saline Washing Affect the Acute Myeloid Leukemia Proteome

by Rebecca Wangen, Elise Aasebø, Andrea Trentani, Stein-Ove Døskeland, Øystein Bruserud, Frode Selheim and Maria Hernandez-Valladares

Int. J. Mol. Sci. 2018, 19(1), 296; https://doi.org/10.3390/ijms19010296 - 19 Jan 2018

Cited by 5 | Viewed by 7718

Abstract

Acute myeloid leukemia (AML) primary cells can be isolated from peripheral blood, suspended with media containing bovine serum and cryoprotectant, and stored in liquid nitrogen before being processed for proteomic analysis by mass spectrometry (MS). The presence of bovine serum and human blood proteins in AML samples can hamper the identifications of proteins, and thereby reduce the proteome coverage of the study. Herein, we have established the effect of phosphate buffered saline (PBS) washing on AML patient samples stored in media. Although PBS washes effectively removed serum and blood contaminants, the saline wash resulted in cell burst and remarkable protein material loss. We also compared different methods to preserve the AML proteome from THP-1 and Molm-13 cell lines before MS analysis: (1) stored in media containing bovine serum and dimethyl sulfoxide (DMSO); (2) stored as dried cell pellets; and (3) stored as cell lysates in 4% sodium dodecyl sulfate (SDS). MS analysis of differently preserved AML cell samples shows that preservation with DMSO produce a high number of fragile cells that will burst during freezing and thawing. Our studies encourage the use of alternative preservation methods for future MS analysis of the AML proteome. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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21 pages, 4916 KiB

Open AccessArticle

A High-Resolution Proteomic Landscaping of Primary Human Dental Stem Cells: Identification of SHED- and PDLSC-Specific Biomarkers

by Vasiliki Taraslia, Stefania Lymperi, Vasiliki Pantazopoulou, Athanasios K. Anagnostopoulos, Issidora S. Papassideri, Efthimia K. Basdra, Marianna Bei, Evangelos G. Kontakiotis, George Th. Tsangaris, Dimitrios J. Stravopodis and Ema Anastasiadou

Int. J. Mol. Sci. 2018, 19(1), 158; https://doi.org/10.3390/ijms19010158 - 5 Jan 2018

Cited by 15 | Viewed by 4996

Abstract

Dental stem cells (DSCs) have emerged as a promising tool for basic research and clinical practice. A variety of adult stem cell (ASC) populations can be isolated from different areas within the dental tissue, which, due to their cellular and molecular characteristics, could give rise to different outcomes when used in potential applications. In this study, we performed a high-throughput molecular comparison of two primary human adult dental stem cell (hADSC) sub-populations: Stem Cells from Human Exfoliated Deciduous Teeth (SHEDs) and Periodontal Ligament Stem Cells (PDLSCs). A detailed proteomic mapping of SHEDs and PDLSCs, via employment of nano-LC tandem-mass spectrometry (MS/MS) revealed 2032 identified proteins in SHEDs and 3235 in PDLSCs. In total, 1516 proteins were expressed in both populations, while 517 were unique for SHEDs and 1721 were exclusively expressed in PDLSCs. Further analysis of the recorded proteins suggested that SHEDs predominantly expressed molecules that are involved in organizing the cytoskeletal network, cellular migration and adhesion, whereas PDLSCs are highly energy-producing cells, vastly expressing proteins that are implicated in various aspects of cell metabolism and proliferation. Applying the Rho-GDI signaling pathway as a paradigm, we propose potential biomarkers for SHEDs and for PDLSCs, reflecting their unique features, properties and engaged molecular pathways. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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2298 KiB

Open AccessArticle

The Venom of the Spine-Bellied Sea Snake (Hydrophis curtus): Proteome, Toxin Diversity and Intraspecific Variation

by Vanessa Neale, Javier Sotillo, Jamie E. Seymour and David Wilson

Int. J. Mol. Sci. 2017, 18(12), 2695; https://doi.org/10.3390/ijms18122695 - 12 Dec 2017

Cited by 16 | Viewed by 5284

Abstract

The spine-bellied sea snake (Hydrophis curtus) is known to cause human deaths, yet its venom composition has not yet been proteomically characterised. An in-depth proteomic analysis was performed on H. curtus venom from two different seasons, January and June, corresponding to adults and subadults, respectively. Venoms from adult and subadult H. curtus individuals were compared using reversed-phase high-performance liquid chromatography (RP-HPLC), matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry and liquid chromatography electrospray ionisation mass spectrometry (LC-ESI-MS) to detect intraspecific variation, and the molecular weight data obtained with ESI-MS were used to assess toxin diversity. RP-HPLC and LC-ESI-MS/MS were used to characterise the venom proteome and estimate the relative abundances of protein families present. The most abundant protein family in January and June venoms is phospholipase A₂ (PLA₂: January 66.7%; June 54.5%), followed by three-finger toxins (3FTx: January 30.4%; June 40.4%) and a minor component of cysteine-rich secretory proteins (CRISP: January 2.5%; June 5%). Trace amounts of snake venom metalloproteinases (SVMP), C-type lectins and housekeeping and regulatory proteins were also found. Although the complexity of the venom is low by number of families present, each family contained a more diverse set of isoforms than previously reported, a finding that may have implications for the development of next-generation sea snake antivenoms. Intraspecific variability was shown to be minor with one obvious exception of a 14,157-Da protein that was present in some January (adult) venoms, but not at all in June (subadult) venoms. There is also a greater abundance of short-chain neurotoxins in June (subadult) venom compared with January (adult) venom. These differences potentially indicate the presence of seasonal, ontogenetic or sexual variation in H. curtus venom. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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4611 KiB

Open AccessArticle

In-Depth Glyco-Peptidomics Approach Reveals Unexpected Diversity of Glycosylated Peptides and Atypical Post-Translational Modifications in Dendroaspis angusticeps Snake Venom

by Michel Degueldre, Julien Echterbille, Nicolas Smargiasso, Christian Damblon, Charlotte Gouin, Gilles Mourier, Nicolas Gilles, Edwin De Pauw and Loïc Quinton

Int. J. Mol. Sci. 2017, 18(11), 2453; https://doi.org/10.3390/ijms18112453 - 18 Nov 2017

Cited by 9 | Viewed by 4209

Abstract

Animal venoms represent a valuable source of bioactive peptides that can be derived into useful pharmacological tools, or even innovative drugs. In this way, the venom of Dendroaspis angusticeps (DA), the Eastern Green Mamba, has been intensively studied during recent years. It mainly contains hundreds of large toxins from 6 to 9 kDa, each displaying several disulfide bridges. These toxins are the main target of venom-based studies due to their valuable activities obtained by selectively targeting membrane receptors, such as ion channels or G-protein coupled receptors. This study aims to demonstrate that the knowledge of venom composition is still limited and that animal venoms contain unexpected diversity and surprises. A previous study has shown that Dendroaspis angusticeps venom contains not only a cocktail of classical toxins, but also small glycosylated peptides. Following this work, a deep exploration of DA glycopeptidome by a dual nano liquid chromatography coupled to electrospray ionization mass spectrometry (nanoLC-ESI-MS) and Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) analyses was initiated. This study reveals unsuspected structural diversity of compounds such as 221 glycopeptides, displaying different glycan structures. Sequence alignments underline structural similarities with natriuretic peptides already characterized in Elapidae venoms. Finally, the presence of an S-cysteinylation and hydroxylation of proline on four glycopeptides, never described to date in snake venoms, is also revealed by proteomics and affined by nuclear magnetic resonance (NMR) experiments. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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Review

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16 pages, 7688 KiB

Open AccessReview

Review on PACAP-Induced Transcriptomic and Proteomic Changes in Neuronal Development and Repair

by Adam Rivnyak, Peter Kiss, Andrea Tamas, Dorottya Balogh and Dora Reglodi

Int. J. Mol. Sci. 2018, 19(4), 1020; https://doi.org/10.3390/ijms19041020 - 29 Mar 2018

Cited by 23 | Viewed by 5440

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with widespread occurrence and diverse biological effects. Among its several different effects, of special importance is the action of PACAP on neuronal proliferation, differentiation and migration, and neuroprotection. The neuroprotective mechanism of PACAP is both direct and indirect, via neuronal and non-neuronal cells. Several research groups have performed transcriptomic and proteomic analysis on PACAP-mediated genes and proteins. Hundreds of proteins have been described as being involved in the PACAP-mediated neuroprotection. In the present review we summarize the few currently available transcriptomic data potentially leading to the proteomic changes in neuronal development and protection. Proteomic studies focusing on the neuroprotective role of PACAP are also reviewed and discussed in light of the most intriguing and promising effect of this neuropeptide, which may possibly have future therapeutic potential. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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12 pages, 634 KiB

Open AccessReview

Venomics-Accelerated Cone Snail Venom Peptide Discovery

by S. W. A. Himaya and Richard J. Lewis

Int. J. Mol. Sci. 2018, 19(3), 788; https://doi.org/10.3390/ijms19030788 - 9 Mar 2018

Cited by 37 | Viewed by 7187

Abstract

Cone snail venoms are considered a treasure trove of bioactive peptides. Despite over 800 species of cone snails being known, each producing over 1000 venom peptides, only about 150 unique venom peptides are structurally and functionally characterized. To overcome the limitations of the traditional low-throughput bio-discovery approaches, multi-omics systems approaches have been introduced to accelerate venom peptide discovery and characterisation. This “venomic” approach is starting to unravel the full complexity of cone snail venoms and to provide new insights into their biology and evolution. The main challenge for venomics is the effective integration of transcriptomics, proteomics, and pharmacological data and the efficient analysis of big datasets. Novel database search tools and visualisation techniques are now being introduced that facilitate data exploration, with ongoing advances in related omics fields being expected to further enhance venomics studies. Despite these challenges and future opportunities, cone snail venomics has already exponentially expanded the number of novel venom peptide sequences identified from the species investigated, although most novel conotoxins remain to be pharmacologically characterised. Therefore, efficient high-throughput peptide production systems and/or banks of miniaturized discovery assays are required to overcome this bottleneck and thus enhance cone snail venom bioprospecting and accelerate the identification of novel drug leads. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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4563 KiB

Open AccessReview

Advances in Proteomic Techniques for Cytokine Analysis: Focus on Melanoma Research

by Helena Kupcova Skalnikova, Jana Cizkova, Jakub Cervenka and Petr Vodicka

Int. J. Mol. Sci. 2017, 18(12), 2697; https://doi.org/10.3390/ijms18122697 - 13 Dec 2017

Cited by 64 | Viewed by 12167

Abstract

Melanoma is a skin cancer with permanently increasing incidence and resistance to therapies in advanced stages. Reports of spontaneous regression and tumour infiltration with T-lymphocytes makes melanoma candidate for immunotherapies. Cytokines are key factors regulating immune response and intercellular communication in tumour microenvironment. Cytokines may be used in therapy of melanoma to modulate immune response. Cytokines also possess diagnostic and prognostic potential and cytokine production may reflect effects of immunotherapies. The purpose of this review is to give an overview of recent advances in proteomic techniques for the detection and quantification of cytokines in melanoma research. Approaches covered span from mass spectrometry to immunoassays for single molecule detection (ELISA, western blot), multiplex assays (chemiluminescent, bead-based (Luminex) and planar antibody arrays), ultrasensitive techniques (Singulex, Simoa, immuno-PCR, proximity ligation/extension assay, immunomagnetic reduction assay), to analyses of single cells producing cytokines (ELISpot, flow cytometry, mass cytometry and emerging techniques for single cell secretomics). Although this review is focused mainly on cancer and particularly melanoma, the discussed techniques are in general applicable to broad research field of biology and medicine, including stem cells, development, aging, immunology and intercellular communication. Full article

(This article belongs to the Special Issue Advances in Proteomic Research for the Characterization of Bioactive Molecules)

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