Special Issue "Protein-Protein Interactions"

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A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (30 November 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Thorsten Berg (Website)

University of Leipzig, Institute for Organic Chemistry, Johannisallee 29, 04103 Leipzig, Germany

Special Issue Information

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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.

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Published Papers (9 papers)

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Research

Jump to: Review

Open AccessArticle Enrichment of Druggable Conformations from Apo Protein Structures Using Cosolvent-Accelerated Molecular Dynamics
Biology 2015, 4(2), 344-366; doi:10.3390/biology4020344
Received: 24 February 2015 / Revised: 27 March 2015 / Accepted: 11 April 2015 / Published: 21 April 2015
Cited by 4 | PDF Full-text (2925 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Here we describe the development of an improved workflow for utilizing experimental and simulated protein conformations in the structure-based design of inhibitors for anti-apoptotic Bcl-2 family proteins. Traditional structure-based approaches on similar targets are often constrained by the sparsity of available structures [...] Read more.
Here we describe the development of an improved workflow for utilizing experimental and simulated protein conformations in the structure-based design of inhibitors for anti-apoptotic Bcl-2 family proteins. Traditional structure-based approaches on similar targets are often constrained by the sparsity of available structures and difficulties in finding lead compounds that dock against flat, flexible protein-protein interaction surfaces. By employing computational docking of known small molecule inhibitors, we have demonstrated that structural ensembles derived from either accelerated MD (aMD) or MD in the presence of an organic cosolvent generally give better scores than those assessed from analogous conventional MD. Furthermore, conformations obtained from combined cosolvent aMD simulations started with the apo-Bcl-xL structure yielded better average and minimum docking scores for known binders than an ensemble of 72 experimental apo- and ligand-bound Bcl-xL structures. A detailed analysis of the simulated conformations indicates that the aMD effectively enhanced conformational sampling of the flexible helices flanking the main Bcl-xL binding groove, permitting the cosolvent acting as small ligands to penetrate more deeply into the binding pocket and shape ligand-bound conformations not evident in conventional simulations. We believe this approach could be useful for identifying inhibitors against other protein-protein interaction systems involving highly flexible binding sites, particularly for targets with less accumulated structural data. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
Open AccessArticle A Structure-Based Classification and Analysis of Protein Domain Family Binding Sites and Their Interactions
Biology 2015, 4(2), 327-343; doi:10.3390/biology4020327
Received: 16 January 2015 / Revised: 24 March 2015 / Accepted: 31 March 2015 / Published: 9 April 2015
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Abstract
While the number of solved 3D protein structures continues to grow rapidly, the structural rules that distinguish protein-protein interactions between different structural families are still not clear. Here, we classify and analyse the secondary structural features and promiscuity of a comprehensive non-redundant [...] Read more.
While the number of solved 3D protein structures continues to grow rapidly, the structural rules that distinguish protein-protein interactions between different structural families are still not clear. Here, we classify and analyse the secondary structural features and promiscuity of a comprehensive non-redundant set of domain family binding sites (DFBSs) and hetero domain-domain interactions (DDIs) extracted from our updated KBDOCK resource. We have partitioned 4001 DFBSs into five classes using their propensities for three types of secondary structural elements (“α” for helices, “β” for strands, and “γ” for irregular structure) and we have analysed how frequently these classes occur in DDIs. Our results show that β elements are not highly represented in DFBSs compared to α and γ elements. At the DDI level, all classes of binding sites tend to preferentially bind to the same class of binding sites and α/β contacts are significantly disfavored. Very few DFBSs are promiscuous: 80% of them interact with just one Pfam domain. About 50% of our Pfam domains bear only one single-partner DFBS and are therefore monogamous in their interactions with other domains. Conversely, promiscuous Pfam domains bear several DFBSs among which one or two are promiscuous, thereby multiplying the promiscuity of the concerned protein. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
Open AccessArticle NPPD: A Protein-Protein Docking Scoring Function Based on Dyadic Differences in Networks of Hydrophobic and Hydrophilic Amino Acid Residues
Biology 2015, 4(2), 282-297; doi:10.3390/biology4020282
Received: 27 November 2014 / Accepted: 16 March 2015 / Published: 24 March 2015
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Abstract
Protein-protein docking (PPD) predictions usually rely on the use of a scoring function to rank docking models generated by exhaustive sampling. To rank good models higher than bad ones, a large number of scoring functions have been developed and evaluated, but the [...] Read more.
Protein-protein docking (PPD) predictions usually rely on the use of a scoring function to rank docking models generated by exhaustive sampling. To rank good models higher than bad ones, a large number of scoring functions have been developed and evaluated, but the methods used for the computation of PPD predictions remain largely unsatisfactory. Here, we report a network-based PPD scoring function, the NPPD, in which the network consists of two types of network nodes, one for hydrophobic and the other for hydrophilic amino acid residues, and the nodes are connected when the residues they represent are within a certain contact distance. We showed that network parameters that compute dyadic interactions and those that compute heterophilic interactions of the amino acid networks thus constructed allowed NPPD to perform well in a benchmark evaluation of 115 PPD scoring functions, most of which, unlike NPPD, are based on some sort of protein-protein interaction energy. We also showed that NPPD was highly complementary to these energy-based scoring functions, suggesting that the combined use of conventional scoring functions and NPPD might significantly improve the accuracy of current PPD predictions. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
Open AccessArticle Easy and Rapid Binding Assay for Functional Analysis of Disulfide-Containing Peptides by a Pull-Down Method Using a Puromycin-Linker and a Cell-Free Translation System
Biology 2015, 4(1), 161-172; doi:10.3390/biology4010161
Received: 20 December 2014 / Revised: 11 February 2015 / Accepted: 17 February 2015 / Published: 2 March 2015
Cited by 1 | PDF Full-text (771 KB) | HTML Full-text | XML Full-text
Abstract
Constrained peptides are an attractive class as affinity reagents or drug leads owing to their excellent binding properties. Many kinds of these peptides, such as cyclic peptides containing disulfide bridges, are found in nature or designed artificially by directed evolution. However, confirming [...] Read more.
Constrained peptides are an attractive class as affinity reagents or drug leads owing to their excellent binding properties. Many kinds of these peptides, such as cyclic peptides containing disulfide bridges, are found in nature or designed artificially by directed evolution. However, confirming the binding properties of the disulfide-rich peptides can be generally difficult, because of oxidative folding problems in the preparation steps. Therefore, a method for evaluating the binding properties of such peptides rapidly and easily is required. Here, we report an easy and rapid method for preparing biotin-attached peptides containing disulfide bridges or a chemical cross-linker using a cell-free translation system and a puromycin-linker, which is applicable to pull-down assays for protein (or peptide) molecular interaction analysis. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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Open AccessCommunication KAP1 is a Novel Substrate for the Arginine Methyltransferase PRMT5
Biology 2015, 4(1), 41-49; doi:10.3390/biology4010041
Received: 28 November 2014 / Accepted: 4 January 2015 / Published: 9 January 2015
Cited by 1 | PDF Full-text (306 KB) | HTML Full-text | XML Full-text
Abstract
KRAB-associated protein 1 (KAP1), the transcriptional corepressor of Kruppel-associated box zinc finger proteins (KRAB-ZFPs), is subjected to multiple post-translational modifications that are involved in fine-tuning of the multiple biological functions of KAP1. In previous papers, we analyzed the KAP1-dependent molecular mechanism of [...] Read more.
KRAB-associated protein 1 (KAP1), the transcriptional corepressor of Kruppel-associated box zinc finger proteins (KRAB-ZFPs), is subjected to multiple post-translational modifications that are involved in fine-tuning of the multiple biological functions of KAP1. In previous papers, we analyzed the KAP1-dependent molecular mechanism of transcriptional repression mediated by ZNF224, a member of the KRAB-ZFP family, and identified the protein arginine methyltransferase PRMT5 as a component of the ZNF224 repression complex. We demonstrated that PRMT5-mediated histone arginine methylation is required to elicit ZNF224 transcriptional repression. In this study, we show that KAP1 interacts with PRMT5 and is a novel substrate for PRMT5 methylation. Also, we present evidence that the methylation of KAP1 arginine residues regulate the KAP1-ZNF224 interaction, thus suggesting that this KAP1 post-translational modification could actively contribute to the regulation of ZNF224-mediated repression. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)

Review

Jump to: Research

Open AccessReview Structural Organization of Enzymes of the Phenylacetate Catabolic Hybrid Pathway
Biology 2015, 4(2), 424-442; doi:10.3390/biology4020424
Received: 10 March 2015 / Revised: 25 May 2015 / Accepted: 29 May 2015 / Published: 12 June 2015
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Abstract
Aromatic compounds are the second most abundant class of molecules on the earth and frequent environmental pollutants. They are difficult to metabolize due to an inert chemical structure, and of all living organisms, only microbes have evolved biochemical pathways that can open [...] Read more.
Aromatic compounds are the second most abundant class of molecules on the earth and frequent environmental pollutants. They are difficult to metabolize due to an inert chemical structure, and of all living organisms, only microbes have evolved biochemical pathways that can open an aromatic ring and catabolize thus formed organic molecules. In bacterial genomes, the phenylacetate (PA) utilization pathway is abundant and represents the central route for degradation of a variety of organic compounds, whose degradation reactions converge at this pathway. The PA pathway is a hybrid pathway and combines the dual features of aerobic metabolism, i.e., usage of both oxygen to open the aromatic ring and of anaerobic metabolism—coenzyme A derivatization of PA. This allows the degradation process to be adapted to fluctuating oxygen conditions. In this review we focus on the structural and functional aspects of enzymes and their complexes involved in the PA degradation by the catabolic hybrid pathway. We discuss the ability of the central PaaABCE monooxygenase to reversibly oxygenate PA, the controlling mechanisms of epoxide concentration by the pathway enzymes, and the similarity of the PA utilization pathway to the benzoate utilization Box pathway and β-oxidation of fatty acids. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
Open AccessReview Recent Advances in the Analysis of Macromolecular Interactions Using the Matrix-Free Method of Sedimentation in the Analytical Ultracentrifuge
Biology 2015, 4(1), 237-250; doi:10.3390/biology4010237
Received: 1 December 2014 / Revised: 8 February 2015 / Accepted: 16 February 2015 / Published: 6 March 2015
PDF Full-text (668 KB) | HTML Full-text | XML Full-text
Abstract
Sedimentation in the analytical ultracentrifuge is a matrix free solution technique with no immobilisation, columns, or membranes required and can be used to study self-association and complex or “hetero”-interactions, stoichiometry, reversibility and interaction strength of a wide variety of macromolecular types and [...] Read more.
Sedimentation in the analytical ultracentrifuge is a matrix free solution technique with no immobilisation, columns, or membranes required and can be used to study self-association and complex or “hetero”-interactions, stoichiometry, reversibility and interaction strength of a wide variety of macromolecular types and across a very large dynamic range (dissociation constants from 10−12 M to 10−1 M). We extend an earlier review specifically highlighting advances in sedimentation velocity and sedimentation equilibrium in the analytical ultracentrifuge applied to protein interactions and mucoadhesion and to review recent applications in protein self-association (tetanus toxoid, agrin), protein-like carbohydrate association (aminocelluloses), carbohydrate-protein interactions (polysaccharide-gliadin), nucleic-acid protein (G-duplexes), nucleic acid-carbohydrate (DNA-chitosan) and finally carbohydrate-carbohydrate (xanthan-chitosan and a ternary polysaccharide complex) interactions. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
Open AccessReview Eukaryotic LYR Proteins Interact with Mitochondrial Protein Complexes
Biology 2015, 4(1), 133-150; doi:10.3390/biology4010133
Received: 12 December 2014 / Accepted: 4 February 2015 / Published: 12 February 2015
Cited by 2 | PDF Full-text (699 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In eukaryotic cells, mitochondria host ancient essential bioenergetic and biosynthetic pathways. LYR (leucine/tyrosine/arginine) motif proteins (LYRMs) of the Complex1_LYR-like superfamily interact with protein complexes of bacterial origin. Many LYR proteins function as extra subunits (LYRM3 and LYRM6) or novel assembly factors (LYRM7, [...] Read more.
In eukaryotic cells, mitochondria host ancient essential bioenergetic and biosynthetic pathways. LYR (leucine/tyrosine/arginine) motif proteins (LYRMs) of the Complex1_LYR-like superfamily interact with protein complexes of bacterial origin. Many LYR proteins function as extra subunits (LYRM3 and LYRM6) or novel assembly factors (LYRM7, LYRM8, ACN9 and FMC1) of the oxidative phosphorylation (OXPHOS) core complexes. Structural insights into complex I accessory subunits LYRM6 and LYRM3 have been provided by analyses of EM and X-ray structures of complex I from bovine and the yeast Yarrowia lipolytica, respectively. Combined structural and biochemical studies revealed that LYRM6 resides at the matrix arm close to the ubiquinone reduction site. For LYRM3, a position at the distal proton-pumping membrane arm facing the matrix space is suggested. Both LYRMs are supposed to anchor an acyl-carrier protein (ACPM) independently to complex I. The function of this duplicated protein interaction of ACPM with respiratory complex I is still unknown. Analysis of protein-protein interaction screens, genetic analyses and predicted multi-domain LYRMs offer further clues on an interaction network and adaptor-like function of LYR proteins in mitochondria. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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Open AccessReview PDZ Domain Recognition: Insight from Human Tax-Interacting Protein 1 (TIP-1) Interaction with Target Proteins
Biology 2015, 4(1), 88-103; doi:10.3390/biology4010088
Received: 25 November 2014 / Revised: 22 January 2015 / Accepted: 23 January 2015 / Published: 5 February 2015
Cited by 2 | PDF Full-text (1011 KB) | HTML Full-text | XML Full-text
Abstract
Cellular signaling is primarily directed via protein-protein interactions. PDZ (PSD-95/Discs large/ZO-1 homologous) domains are well known protein-protein interaction modules involved in various key signaling pathways. Human Tax-interacting protein 1 (TIP-1), also known as glutaminase interaction protein (GIP), is a Class I PDZ [...] Read more.
Cellular signaling is primarily directed via protein-protein interactions. PDZ (PSD-95/Discs large/ZO-1 homologous) domains are well known protein-protein interaction modules involved in various key signaling pathways. Human Tax-interacting protein 1 (TIP-1), also known as glutaminase interaction protein (GIP), is a Class I PDZ domain protein that recognizes the consensus binding motif X-S/T-X-V/I/L-COOH of the C-terminus of its target proteins. We recently reported that TIP-1 not only interacts via the C-terminus of its target partner proteins but also recognizes an internal motif defined by the consensus sequence S/T-X-V/L-D in the target protein. Identification of new target partners containing either a C-terminal or internal recognition motif has rapidly expanded the TIP-1 protein interaction network. TIP-1 being composed solely of a single PDZ domain is unique among PDZ containing proteins. Since it is involved in many important signaling pathways, it is a possible target for drug design. In this mini review, we have discussed human TIP-1, its structure, mechanism of function, its interactions with target proteins containing different recognition motifs, and its involvement in human diseases. Understanding the molecular mechanisms of TIP-1 interactions with distinct target partners and their role in human diseases will be useful for designing novel therapeutics. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Article
Title: A pull-down method for an intra-cross linked peptide with a cell-free translation system
Authors: Yutaro Tanemura, Yuki Mochizuki, Shigeyuki Kumachi, Naoto Nemoto
Affiliations: Graduate School of Science and Engineering, Saitama University, Saitama, Japan; E-Mail: nemoto@fms.saitama-u.ac.jp
Abstract: Constrained peptides are an attractive class as affinity regents or drug leads owing to their exhibit excellent binding properties. Many kinds of constrained peptides, such as cyclic peptides, have been found in nature or designed artificially by directed evolution. However, confirming binding properties of the constrained peptides can generally be troublesome because the synthesis of constrained peptides is more complicated in comparison with linear peptides. In this paper, we showed that biotinylated constrained peptides containing a disulfide bridge or a chemical cross-linking could be synthesized using a cell-free translation system and analyzed with a puromycin-linker in the manner of pull-down assay method.

Type of paper: Review
Title: Eukaryotic LYR proteins interact with ancient mitochondrial protein complexes
Author: Heike Angerer
Affiliation: Goethe University Frankfurt, Medical School, Institute of Biochemistry II, Structural Bioenergetics Group, Frankfurt am Main, Germany; E-Mail: Angerer@em.uni-frankfurt.de
Abstract: In eukaryotic cells mitochondria host ancient essential bioenergetic and biosynthetic pathways that are under nuclear control. LYR (leucine/tyrosine/arginine) motif proteins (LYRMs) of the Complex1_LYR-like superfamily interact with protein complexes of alpha-proteobacteria origin. Many LYR proteins function as extra subunits or novel assembly factors of the oxidative phosphorylation (OXPHOS) core complexes. Structural insights about complex I accessory subunits LYRM6 and LYRM3 have been provided by structural analyses of EM and X-ray structures of complex I from bovine and the yeast Yarrowia lipolytica, respectively. Both LYRMs anchor independently an acyl carrier protein (ACPM) to complex I. The function of this duplicated protein interaction of ACPM with respiratory complex I is still unknown. Analysis of protein-protein interaction screens, genetic analyses and predicted multi-domain LYRMs offer further clues on an interaction network of LYR proteins in mitochondria.


Title: KAP1 is a novel substrate for the arginine methyltransferase PRMT5
Authors: Roberta di Caprio, Michela Ciano, Giorgia Montano, Paola Costanzo and Elena Cesaro
Affiliations: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, via S. Pansini 5, Naples 80131, Italy; E-Mail: paola.costanzo@unina.it
Abstract: KAP1, the transcriptional corepressor of Kruppel-associated box zinc finger proteins (KRAB-ZFPs), is subjected to multiple post-translational modifications that are involved in fine-tuning of its multiple biological functions.
We previously identified the protein arginine methyltransferase PRMT5 as a component of repression complex mediated by the KRAB-ZFP ZNF224. In this study, we show that KAP1 interacts with PRMT5 and is a novel substrate for PRMT5 methylation. Also, we present evidence that the methylation of KAP1 arginine residues regulate the KAP1-ZNF224 interaction, thus suggesting that this KAP1 post-transcriptional modification could actively contribute to the regulation of ZNF224-mediated repression.

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