scholarly journals Histidine, the less interactive cousin of arginine

2019 ◽  
Vol 25 (2) ◽  
pp. 212-218 ◽  
Author(s):  
Ludovic Muller ◽  
Shelley N Jackson ◽  
Amina S Woods
Keyword(s):  
Electrostatic Interactions ◽  
Noncovalent Complex ◽  
Salt Bridge ◽  
Amino Acid Residues ◽  
Noncovalent Complexes ◽  
Post Translational Modifications ◽  
Noncovalent Bonds ◽  
Esi Mass Spectrometry ◽  
Main Factors ◽  
Biomolecular Conformation

Electrostatic interactions are one of the main factors influencing biomolecular conformation. The formation of noncovalent complexes by electrostatic interactions is governed by certain amino acid residues and post-translational modifications. It has been demonstrated that adjacent arginine forms noncovalent complex with phosphate; however, histidine noncovalent complexes have rarely been investigated. In the present work, we compare the interaction between basic epitopes (NLRRITRVN, SHHGLHSTPD) and diverse acidic and aromatic-rich peptides using both MALDI and ESI Mass spectrometry. We show that adjacent histidines can also form stable noncovalent bonds and that those bonds are probably formed by a salt bridge between the phosphate or the acid residues and the histidines. However, noncovalent complexes with the arginine epitopes form more readily and are stronger than those with histidine-containing epitopes.

Dicarbonyl derived post-translational modifications: chemistry bridging biology and aging-related disease

2020 ◽  
Vol 64 (1) ◽  
pp. 97-110
Author(s):  
Christian Sibbersen ◽  
Mogens Johannsen
Keyword(s):  
Mass Spectrometry ◽  
Future Research ◽  
Amino Acid Residues ◽  
Post Translational Modification ◽  
Dicarbonyl Compounds ◽  
Protein Targets ◽  
Post Translational Modifications ◽  
Reactive Protein ◽  
Glycation End Products ◽  
Direct Mass Spectrometry

Abstract In living systems, nucleophilic amino acid residues are prone to non-enzymatic post-translational modification by electrophiles. α-Dicarbonyl compounds are a special type of electrophiles that can react irreversibly with lysine, arginine, and cysteine residues via complex mechanisms to form post-translational modifications known as advanced glycation end-products (AGEs). Glyoxal, methylglyoxal, and 3-deoxyglucosone are the major endogenous dicarbonyls, with methylglyoxal being the most well-studied. There are several routes that lead to the formation of dicarbonyl compounds, most originating from glucose and glucose metabolism, such as the non-enzymatic decomposition of glycolytic intermediates and fructosyl amines. Although dicarbonyls are removed continuously mainly via the glyoxalase system, several conditions lead to an increase in dicarbonyl concentration and thereby AGE formation. AGEs have been implicated in diabetes and aging-related diseases, and for this reason the elucidation of their structure as well as protein targets is of great interest. Though the dicarbonyls and reactive protein side chains are of relatively simple nature, the structures of the adducts as well as their mechanism of formation are not that trivial. Furthermore, detection of sites of modification can be demanding and current best practices rely on either direct mass spectrometry or various methods of enrichment based on antibodies or click chemistry followed by mass spectrometry. Future research into the structure of these adducts and protein targets of dicarbonyl compounds may improve the understanding of how the mechanisms of diabetes and aging-related physiological damage occur.

scholarly journals SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Amino Acid Residues ◽  
Dibasic Amino Acid ◽  
Novel Target ◽  
Function Relationship ◽  
Dynamics Simulations

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.

scholarly journals Three Structural Features of Functional Food Components and Herbal Medicine with Amyloid β42 Anti-Aggregation Properties

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2125 ◽  
Author(s):  
Kazuma Murakami ◽  
Kazuhiro Irie
Keyword(s):  
Amino Acid ◽  
Functional Food ◽  
Structural Characteristics ◽  
Salt Bridge ◽  
Basic Amino Acid ◽  
Structural Features ◽  
Amino Acid Residues ◽  
Treatment And Prevention ◽  
Food Components ◽  
Underlying Mechanisms

Aggregation of amyloid β42 (Aβ42) is one of the hallmarks of Alzheimer’s disease (AD). There are numerous naturally occurring products that suppress the aggregation of Aβ42, but the underlying mechanisms remain to be elucidated. Based on NMR and MS spectroscopic analysis, we propose three structural characteristics found in natural products required for the suppressive activity against Aβ42 aggregation (i.e., oligomerization by targeting specific amino acid residues on this protein). These characteristics include (1) catechol-type flavonoids that can form Michael adducts with the side chains of Lys16 and 28 in monomeric Aβ42 through flavonoid autoxidation; (2) non-catechol-type flavonoids with planarity due to α,β-unsaturated carbonyl groups that can interact with the intermolecular β-sheet region in Aβ42 aggregates, especially aromatic rings such as those of Phe19 and 20; and (3) carboxy acid derivatives with triterpenoid or anthraquinoid that can generate a salt bridge with basic amino acid residues such as Lys16 and 28 in the Aβ42 dimer or trimer. Here, we summarize the recent body of knowledge concerning amyloidogenic inhibitors, particularly in functional food components and Kampo medicine, and discuss their application in the treatment and prevention of AD.

Modèle topologique de la structure d’un antiport vacuolaire de type NHX chez la vigne cultivée (Vitis vinifera)

Botany ◽  
2009 ◽  
Vol 87 (3) ◽  
pp. 339-347 ◽  
Author(s):  
Mohsen Hanana ◽  
Olivier Cagnac ◽  
Ahmed Mliki ◽  
Eduardo Blumwald
Keyword(s):  
Amino Acid ◽  
Vitis Vinifera ◽  
Molecular Mass ◽  
Electrostatic Interactions ◽  
Functional Characterization ◽  
Terminal Region ◽  
Vitis Vinifera L ◽  
Amino Acid Residues ◽  
Transmembrane Segments ◽  
Α Helix

After identifying and isolating a grapevine ( Vitis vinifera L.) NHX vacuolar antiporter and before initializing functional genomic studies, we juged necessary to acquire a minimum of knowledge about the VvNHX1 protein. Thus, we realized a bioinformatic analysis to determine its basic characteristics and to get structural informations that could guide us through the functional characterization. We have determined important physico-chemical parameters (molecular mass, isoelectric point, hydrophobic regions, etc.) and obtained interesting structural data (primary, secondary, and tertiary structures; conserved domains and interaction motives; etc.). The VvNHX1 gene, which encodes this 541 amino-acid protein with a predicted molecular mass of 60 kDa, is made of 14 exons and measures 6.5 kb. The amino-acidic composition of this protein is very important, in particular, for the establishment of the α-helix structure, which represents more than 50% of the protein, but also for charge distribution, which generates critical electrostatic interactions for the ionic flux. The secondary structure of VvNHX1 contains multiple transmembrane α-helix segments that are made of hydrophobic amino-acid residues, thus facilitating its insertion in the membrane. Globally, VvNHX1 has one hydrophobic N-terminal region, made of 10 transmembrane segments with 440 amino-acid residues, and one hydrophilic C-terminal region, made of 100 residues. The region located between the fourth and fifth transmembrane segments represents, with its structure mainly helicoidal and the presence of a favourable electrostatic environment, the pore where cation flux is performed across the membrane. VvNHX1 contains various interaction domains as well as several putative posttranslational modification sites, mainly at the C-terminus but also at the N-terminus, that play an important part in regulating protein activities, influence protein structural stability, or interact with other proteins or signalling molecules.

scholarly journals Mapping of the Active Site of Recombinant Human Erythropoietin

Blood ◽  
1997 ◽  
Vol 89 (2) ◽  
pp. 493-502 ◽  
Author(s):  
Steve Elliott ◽  
Tony Lorenzini ◽  
David Chang ◽  
Jack Barzilay ◽  
Evelyne Delorme
Keyword(s):  
Receptor Binding ◽  
Recombinant Human Erythropoietin ◽  
Electrostatic Interactions ◽  
Binding Activity ◽  
Amino Acid Residues ◽  
Epo Receptor ◽  
Human Erythropoietin ◽  
Biologic Activity ◽  
Identify Amino Acid

Abstract Recombinant human erythropoietin (rHuEPO) variants have been constructed to identify amino acid residues important for biological activity. Immunoassays were used to determine the effect of each mutation on rHuEPO folding. With this strategy, we could distinguish between mutations that affected bioactivity directly and those that affected bioactivity because the mutation altered rHuEPO conformation. Four regions were found to be important for bioactivity: amino acids 11 to 15, 44 to 51, 100 to 108, and 147 to 151. EPO variants could be divided into two groups according to the differential effects on EPO receptor binding activity and in vitro biologic activity. This suggests that rHuEPO has two separate receptor binding sites. Mutations in basic residues reduced the biologic activity, whereas mutations in acidic residues did not. This suggests that electrostatic interactions between rHuEPO and the human EPO receptor may involve positive charges on rHuEPO.

MAPRes: Mining association patterns among preferred amino acid residues in the vicinity of amino acids targeted for post-translational modifications

PROTEOMICS ◽  
2008 ◽  
Vol 8 (10) ◽  
pp. 1954-1958 ◽  
Author(s):  
Ishtiaq Ahmad ◽  
Wajahat M. Qazi ◽  
Ahmed Khurshid ◽  
Munir Ahmad ◽  
Daniel C. Hoessli ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Residues ◽  
Association Patterns ◽  
Post Translational Modifications

scholarly journals Intra-helical salt bridge contribution to membrane protein insertion

2021 ◽  
Author(s):  
Gerard Duart ◽  
John Lamb ◽  
Arne Elofsson ◽  
Ismael Mingarro
Keyword(s):  
Amino Acids ◽  
Membrane Protein ◽  
Electrostatic Interactions ◽  
Salt Bridge ◽  
Protein Stabilization ◽  
Membrane Insertion ◽  
Salt Bridges ◽  
Protein Insertion

ABSTRACTSalt bridges between negatively (D, E) and positively charged (K, R, H) amino acids play an important role in protein stabilization. This has a more prevalent effect in membrane proteins where polar amino acids are exposed to a very hydrophobic environment. In transmembrane (TM) helices the presence of charged residues can hinder the insertion of the helices into the membrane. This can sometimes be avoided by TM region rearrangements after insertion, but it is also possible that the formation of salt bridges could decrease the cost of membrane integration. However, the presence of intra-helical salt bridges in TM domains and their effect on insertion has not been properly studied yet. In this work, we use an analytical pipeline to study the prevalence of charged pairs of amino acid residues in TM α-helices, which shows that potentially salt-bridge forming pairs are statistically over-represented. We then selected some candidates to experimentally determine the contribution of these electrostatic interactions to the translocon-assisted membrane insertion process. Using both in vitro and in vivo systems, we confirm the presence of intra-helical salt bridges in TM segments during biogenesis and determined that they contribute between 0.5-0.7 kcal/mol to the apparent free energy of membrane insertion (ΔGapp). Our observations suggest that salt bridge interactions can be stabilized during translocon-mediated insertion and thus could be relevant to consider for the future development of membrane protein prediction software.

scholarly journals PTMphinder: an R package for PTM site localization and motif extraction from proteomic datasets

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7046 ◽  
Author(s):  
Jacob M. Wozniak ◽  
David J. Gonzalez
Keyword(s):  
R Package ◽  
Data Sets ◽  
Amino Acid Residues ◽  
Post Translational Modifications ◽  
Specific Amino Acid ◽  
Proteomic Data ◽  
Wide Range ◽  
Site Localization ◽  
Programming Knowledge ◽  
Beta Testing

Background Mass-spectrometry-based proteomics is a prominent field of study that allows for the unbiased quantification of thousands of proteins from a particular sample. A key advantage of these techniques is the ability to detect protein post-translational modifications (PTMs) and localize them to specific amino acid residues. These approaches have led to many significant findings in a wide range of biological disciplines, from developmental biology to cancer and infectious diseases. However, there is a current lack of tools available to connect raw PTM site information to biologically meaningful results in a high-throughput manner. Furthermore, many of the available tools require significant programming knowledge to implement. Results The R package PTMphinder was designed to enable researchers, particularly those with minimal programming background, to thoroughly analyze PTMs in proteomic data sets. The package contains three functions: parseDB, phindPTMs and extractBackground. Together, these functions allow users to reformat proteome databases for easier analysis, localize PTMs within full proteins, extract motifs surrounding the identified sites and create proteome-specific motif backgrounds for statistical purposes. Beta-testing of this R package has demonstrated its simplicity and ease of integration with existing tools. Conclusion PTMphinder empowers researchers to fully analyze and interpret PTMs derived from proteomic data. This package is simple enough for researchers with limited programming experience to understand and implement. The data produced from this package can inform subsequent research by itself and also be used in conjunction with other tools, such as motif-x, for further analysis.

scholarly journals Delving Deep into the Structural Aspects of the BPro28-BLys29 Exchange in Insulin Lispro: A Structural Biophysical Lesson

2020 ◽  
Author(s):  
Wei Li
Keyword(s):  
Insulin Lispro ◽  
Electrostatic Interactions ◽  
Regular Insulin ◽  
Site Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Polar Amino Acid ◽  
Binding Interface ◽  
Biophysical Mechanism ◽  
Fast Acting ◽  
Structural Aspects

Insulin lispro was the first fast acting insulin analogue to obtain regulatory approval for therapeutic use. This article puts forward a novel biophysical mechanism where the net impact of the simple B28Pro-B29Lys exchange from regular insulin to insulin lispro is the establishment of a novel set of interfacial electrostatic interactions between Lys28 of insulin lispro and Asp12 of insulin receptor (IR). In addition, a set of structural analysis was presented in this article to further strengthen the binding of insulin lispro to IR, where two polar amino acid residues (Gln51 and Asn74 of insulin lispro) were put forward as two potential targets for site-directed mutagenesis of insulin lispro at its binding interface with IR.

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