Predicting the involvement of polyQ- and polyA in protein-protein interactions by their amino acid context.

Homorepeats, specifically polyglutamine (polyQ) and polyalanine (polyA), are often implicated in protein-protein interactions (PPIs). So far, a method to predict the participation of homorepeats in protein interactions is lacking. We propose a machine learning approach to identify PPI-involved polyQ and polyA regions within the human proteome based on known interacting regions.

Homorepeat variability within the human population.

Genetic variation within populations plays a crucial role in driving evolution. Unlike the average protein sequence, the evolution of homorepeats can be influenced by DNA replication slippage, when DNA polymerases either add or skip repeats of nucleotides. While there are some diseases known to be caused by abnormal changes in the length of amino acid homorepeats, naturally occurring variations in homorepeat length remain relatively unexplored.

Structured Tandem Repeats in Protein Interactions.

Tandem repeats (TRs) in protein sequences are consecutive, highly similar sequence motifs. Some types of TRs fold into structural units that pack together in ensembles, forming either an (open) elongated domain or a (closed) propeller, where the last unit of the ensemble packs against the first one. Here, we examine TR proteins (TRPs) to see how their sequence, structure, and evolutionary properties favor them for a function as mediators of protein interactions.

The Endocrine Phenotype Induced by Pediatric Adrenocortical Tumors Is Age- and Sex-Dependent.

Context: Adrenocortical carcinomas are very rare malignancies in childhood associated with poor outcome in advanced disease. Most adrenocortical tumors (ACT) are functional, causing signs and symptoms of adrenal hormone excess. In most studies, endocrine manifestations were reported 4 to 6 months prior to diagnosis.

The nucleotide landscape of polyXY regions.

PolyXY regions are compositionally biased regions composed of two different amino acids. They are classified according to the arrangement of the two amino acid types 'X' and 'Y' into direpeats (composed of alternating amino acids, e.g.

Structure-function relationships in protein homorepeats.

Homorepeats (or polyX), protein segments containing repetitions of the same amino acid, are abundant in proteomes from all kingdoms of life and are involved in crucial biological functions as well as several neurodegenerative and developmental diseases. Mainly inserted in disordered segments of proteins, the structure/function relationships of homorepeats remain largely unexplored. In this review, we summarize present knowledge for the most abundant homorepeats, highlighting the role of the inherent structure and the conformational influence exerted by their flanking regions.

Locally Advanced Adrenocortical Carcinoma in Children and Adolescents-Enigmatic and Challenging Cases.

Background: Locally advanced tumors account for approximately 50% of children and adolescents with adrenocortical carcinoma (ACC), and of these, up to 50% relapse. We explored the five-item microscopic score and the pS-GRAS score for guiding management.

Methods: Data from children and adolescents with COG stage II and III ACC registered in the MET studies were included.

A STRP-ed definition of Structured Tandem Repeats in Proteins.

Tandem Repeat Proteins (TRPs) are a class of proteins with repetitive amino acid sequences that have been studied extensively for over two decades. Different features at the level of sequence, structure, function and evolution have been attributed to them by various authors. And yet many of its salient features appear only when looking at specific subclasses of protein tandem repeats.

Evolutionary Study of Protein Short Tandem Repeats in Protein Families.

Tandem repeats in proteins are patterns of residues repeated directly adjacent to each other. The evolution of these repeats can be assessed by using groups of homologous sequences, which can help pointing to events of unit duplication or deletion. High pressure in a protein family for variation of a given type of repeat might point to their function.

Protein repeats evolve and emerge in giant viruses.

Nucleocytoplasmatic large DNA viruses (NCLDVs or giant viruses) stand out because of their relatively large genomes encoding hundreds of proteins. These species give us an unprecedented opportunity to study the emergence and evolution of repeats in protein sequences. On the one hand, as viruses, these species have a restricted set of functions, which can help us better define the functional landscape of repeats.

Functional Tuning of Intrinsically Disordered Regions in Human Proteins by Composition Bias.

Intrinsically disordered regions (IDRs) in protein sequences are flexible, have low structural constraints and as a result have faster rates of evolution. This lack of evolutionary conservation greatly limits the use of sequence homology for the classification and functional assessment of IDRs, as opposed to globular domains. The study of IDRs requires other properties for their classification and functional prediction.

Regions with two amino acids in protein sequences: A step forward from homorepeats into the low complexity landscape.

Low complexity regions (LCRs) differ in amino acid composition from the background provided by the corresponding proteomes. The simplest LCRs are homorepeats (or polyX), regions composed of mostly-one amino acid type. Extensive research has been done to characterize homorepeats, and their taxonomic, functional and structural features depend on the amino acid type and sequence context.

The sequence context in poly-alanine regions: structure, function and conservation.

Motivation: Poly-alanine (polyA) regions are protein stretches mostly composed of alanines. Despite their abundance in eukaryotic proteomes and their association to nine inherited human diseases, the structural and functional roles exerted by polyA stretches remain poorly understood. In this work we study how the amino acid context in which polyA regions are settled in proteins influences their structure and function.

Low Complexity Induces Structure in Protein Regions Predicted as Intrinsically Disordered.

There is increasing evidence that many intrinsically disordered regions (IDRs) in proteins play key functional roles through interactions with other proteins or nucleic acids. These interactions often exhibit a context-dependent structural behavior. We hypothesize that low complexity regions (LCRs), often found within IDRs, could have a role in inducing local structure in IDRs.

Key factors for effective mitotane therapy in children with adrenocortical carcinoma.

Adjuvant treatment with mitotane and chemotherapy is recommended for paediatric advanced and metastatic adrenocortical carcinoma (ACC). Yet, questions on the indication, dosage, and length of therapy are unanswered. Data from the German Paediatric Oncology Haematology-Malignant Endocrine Tumour studies were analysed retrospectively for patients receiving mitotane during first- and/or second-line therapy.

Analysis of Huntington's Disease Modifiers Using the Hyperbolic Mapping of the Protein Interaction Network.

Huntington's disease (HD) is caused by the production of a mutant huntingtin (HTT) with an abnormally long poly-glutamine (polyQ) tract, forming aggregates and inclusions in neurons. Previous work by us and others has shown that an increase or decrease in polyQ-triggered aggregates can be passive simply due to the interaction of proteins with the aggregates. To search for proteins with active (functional) effects, which might be more effective in finding therapies and mechanisms of HD, we selected among the proteins that interact with HTT a total of 49 pairs of proteins that, while being paralogous to each other (and thus expected to have similar passive interaction with HTT), are located in different regions of the protein interaction network (suggesting participation in different pathways or complexes).

Annotation and Analysis of 3902 Odorant Receptor Protein Sequences from 21 Insect Species Provide Insights into the Evolution of Odorant Receptor Gene Families in Solitary and Social Insects.

The gene family of insect olfactory receptors (ORs) has expanded greatly over the course of evolution. ORs enable insects to detect volatile chemicals and therefore play an important role in social interactions, enemy and prey recognition, and foraging. The sequences of several thousand ORs are known, but their specific function or their ligands have only been identified for very few of them.

PolyX2: Fast Detection of Homorepeats in Large Protein Datasets.

Homorepeat sequences, consecutive runs of identical amino acids, are prevalent in eukaryotic proteins. It has become necessary to annotate and evaluate this feature in entire proteomes. The definition of what constitutes a homorepeat is not fixed, and different research approaches may require different definitions; therefore, flexible approaches to analyze homorepeats in complete proteomes are needed.

Between Interactions and Aggregates: The PolyQ Balance.

Polyglutamine (polyQ) regions are highly abundant consecutive runs of glutamine residues. They have been generally studied in relation to the so-called polyQ-associated diseases, characterized by protein aggregation caused by the expansion of the polyQ tract via a CAG-slippage mechanism. However, more than 4,800 human proteins contain a polyQ, and only nine of these regions are known to be associated with disease.

REP2: A Web Server to Detect Common Tandem Repeats in Protein Sequences.

Ensembles of tandem repeats (TRs) in protein sequences expand rapidly to form domains well suited for interactions with proteins. For this reason, they are relatively frequent. Some TRs have known structures and therefore it is advantageous to predict their presence in a protein sequence.

The Conservation of Low Complexity Regions in Bacterial Proteins Depends on the Pathogenicity of the Strain and Subcellular Location of the Protein.

Low complexity regions (LCRs) in proteins are characterized by amino acid frequencies that differ from the average. These regions evolve faster and tend to be less conserved between homologs than globular domains. They are not common in bacteria, as compared to their prevalence in eukaryotes.

Avoided motifs: short amino acid strings missing from protein datasets.

According to the amino acid composition of natural proteins, it could be expected that all possible sequences of three or four amino acids will occur at least once in large protein datasets purely by chance. However, in some species or cellular context, specific short amino acid motifs are missing due to unknown reasons. We describe these as Avoided Motifs, short amino acid combinations missing from biological sequences.

The Role of Low Complexity Regions in Protein Interaction Modes: An Illustration in Huntingtin.

Low complexity regions (LCRs) are very frequent in protein sequences, generally having a lower propensity to form structured domains and tending to be much less evolutionarily conserved than globular domains. Their higher abundance in eukaryotes and in species with more cellular types agrees with a growing number of reports on their function in protein interactions regulated by post-translational modifications. LCRs facilitate the increase of regulatory and network complexity required with the emergence of organisms with more complex tissue distribution and development.