Insilico Analysis of Post-Translational Modifications in DRD2 Receptor Protein in Schizophrenic Patients

Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.

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

Essays in Biochemistry ◽

10.1042/ebc20190057 ◽

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.

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The challenge of detecting modifications on proteins

Essays in Biochemistry ◽

10.1042/ebc20190055 ◽

2020 ◽

Vol 64 (1) ◽

pp. 135-153 ◽

Cited By ~ 1

Author(s):

Lauren Elizabeth Smith ◽

Adelina Rogowska-Wrzesinska

Keyword(s):

Mass Spectrometry ◽

Protein Function ◽

Chemical Properties ◽

Lysine Acetylation ◽

Mass Determination ◽

Post Translational Modifications ◽

Site Specific ◽

The Common

Abstract Post-translational modifications (PTMs) are integral to the regulation of protein function, characterising their role in this process is vital to understanding how cells work in both healthy and diseased states. Mass spectrometry (MS) facilitates the mass determination and sequencing of peptides, and thereby also the detection of site-specific PTMs. However, numerous challenges in this field continue to persist. The diverse chemical properties, low abundance, labile nature and instability of many PTMs, in combination with the more practical issues of compatibility with MS and bioinformatics challenges, contribute to the arduous nature of their analysis. In this review, we present an overview of the established MS-based approaches for analysing PTMs and the common complications associated with their investigation, including examples of specific challenges focusing on phosphorylation, lysine acetylation and redox modifications.

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Brain electric microstates in schizophrenic patients display deviant adaptation of the functional brain state

Electroencephalography and Clinical Neurophysiology ◽

10.1016/s0013-4694(97)88377-4 ◽

1997 ◽

Vol 103 (1) ◽

pp. 92

Author(s):

T Koenig

Keyword(s):

Brain State ◽

Functional Brain ◽

Schizophrenic Patients

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Post-translational Modifications in Plants

10.1017/cbo9780511600401 ◽

1993 ◽

Cited By ~ 3

Keyword(s):

Post Translational Modifications

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The self and schizophrenia: a cognitive approach

Swiss Journal of Psychology ◽

10.1024//1421-0185.62.1.45 ◽

2003 ◽

Vol 62 (1) ◽

pp. 45-51 ◽

Cited By ~ 5

Author(s):

Marek Nieznanski

Keyword(s):

Normal Subjects ◽

Control Group ◽

Cognitive Approach ◽

Schizophrenic Patients ◽

Self Schema ◽

Persons With Schizophrenia ◽

Basic Features ◽

Trait Words ◽

Patients Experience ◽

Normal Controls

The aim of the study was to explore the basic features of self-schema in persons with schizophrenia. Thirty two schizophrenic patients and 32 normal controls were asked to select personality trait words from a check-list that described themselves, themselves as they were five years ago, and what most people are like. Compared with the control group, participants from the experimental group chose significantly more adjectives that were common to descriptions of self and others, and significantly less that were common to self and past-self descriptions. These results suggest that schizophrenic patients experience their personality as changing over time much more than do healthy subjects. Moreover, their self-representation seems to be less differentiated from others-representation and less clearly defined than in normal subjects.

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An ERP Investigation of Semantic Priming, Repetition Priming, and Negative Priming in Schizophrenic Patients

Journal of Psychophysiology ◽

10.1027/0269-8803.20.3.195 ◽

2006 ◽

Vol 20 (3) ◽

pp. 195-211 ◽

Cited By ~ 7

Author(s):

Michael Wagner ◽

Lioba Baving ◽

Patrick Berg ◽

Rudolf Cohen ◽

Brigitte Rockstroh

Keyword(s):

Negative Priming ◽

Repetition Priming ◽

Event Related Potentials ◽

Decision Task ◽

Positive Priming ◽

Retrieval Processes ◽

Schizophrenic Patients ◽

Related Potentials ◽

Late Positive Complex ◽

Automatic Memory

The processing of attended and nonattended stimuli in schizophrenic patients was examined with event-related potentials (ERPs) in a lexical decision task. In positive semantic and repetition priming the N400 amplitude did not differ between a group of 17 medicated schizophrenic patients and a group of 20 matched healthy controls. However, negative priming affected the N400 only in controls. Reaction time effects were dissociated from these ERP effects, with patients showing stronger positive priming than controls but identical negative priming. The semantic processes related to the N400 appear to be intact in schizophrenic patients, but patients seem to incorporate less context information (about the nonattended prime) in their episodic memory traces. A stronger increase of the posterior late positive complex in parallel to the stronger positive priming in schizophrenic patients may reflect relatively stronger automatic memory retrieval processes in patients.

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The Antiaggressive Action of Combined Haloperidol-Propranolol Treatment in Schizophrenia

European Psychologist ◽

10.1027//1016-9040.5.4.312 ◽

2000 ◽

Vol 5 (4) ◽

pp. 312-325 ◽

Cited By ~ 9

Author(s):

Gadi Maoz ◽

Daniel Stein ◽

Sorin Meged ◽

Larisa Kurzman ◽

Joseph Levine ◽

...

Keyword(s):

Rating Scales ◽

Double Blind ◽

Propranolol Group ◽

Schizophrenic Patients ◽

Propranolol Treatment ◽

Simultaneous Decrease ◽

The Mean ◽

Haloperidol Treatment ◽

To Receive ◽

Drug Free

Psychopharmacological interventions for managing aggression in schizophrenia have thus far yielded inconsistent results. This study evaluates the antiaggressive efficacy of combined haloperidol-propranolol treatment. Thirty-four newly admitted schizophrenic patients were studied in a controlled double-blind trial. Following a 3-day drug-free period and 7 days of haloperidol treatment, patients were randomly assigned to receive either haloperidol-propranolol or haloperidol-placebo for eight consecutive weeks. Doses of medications were adjusted as necessary; biperiden was administered if required. Rating scales were applied to assess aggression, anger, psychosis, depression, anxiety and extrapyramidal symptoms. The mean daily dose of haloperidol was 21 mg (SD = 6.4) in the research group and 29 mg (SD = 6.9) in the controls. Mean and maximal daily doses of propranolol were 159 mg (SD = 61) and 192 mg (SD = 83), and of placebo, 145 mg (SD = 50) and 180 mg (SD = 70), respectively. Compared with the controls, the scores for the research patients decreased significantly from baseline, particularly after 4 weeks of treatment, for some dimensions of anger, psychosis, anxiety, and neuroleptic-induced parkinsonism. A tendency for reduced aggression was shown in the combined haloperidol-propranolol group for some dimensions but not others. These patients also required significantly less biperiden. The tendency toward elevated antiaggressive effect of combined haloperidol-propranolol treatment compared to haloperidol alone may be explained by a simultaneous decrease in aggression, psychotic symptomatology, and anxiety.

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