67 research outputs found
Local Function Conservation in Sequence and Structure Space
We assess the variability of protein function in protein sequence and structure space. Various regions in this space exhibit considerable difference in the local conservation of molecular function. We analyze and capture local function conservation by means of logistic curves. Based on this analysis, we propose a method for predicting molecular function of a query protein with known structure but unknown function. The prediction method is rigorously assessed and compared with a previously published function predictor. Furthermore, we apply the method to 500 functionally unannotated PDB structures and discuss selected examples. The proposed approach provides a simple yet consistent statistical model for the complex relations between protein sequence, structure, and function. The GOdot method is available online (http://godot.bioinf.mpi-inf.mpg.de)
Identifying and Characterizing a Novel Protein Kinase STK35L1 and Deciphering Its Orthologs and Close-Homologs in Vertebrates
The human kinome containing 478 eukaryotic protein kinases has over 100 uncharacterized kinases with unknown substrates and biological functions. The Ser/Thr kinase 35 (STK35, Clik1) is a member of the NKF 4 (New Kinase Family 4) in the kinome with unknown substrates and biological functions. Various high throughput studies indicate that STK35 could be involved in various human diseases such as colorectal cancer and malaria. In this study, we found that the previously published coding sequence of the STK35 gene is incomplete. The newly identified sequence of the STK35 gene codes for a protein of 534 amino acids with a N-terminal elongation of 133 amino acids. It has been designated as STK35L (STK35 long). Since it is the first of further homologous kinases we termed it as STK35L1. The STK35L1 protein (58 kDa on SDS-PAGE), but not STK35 (44 kDa), was found to be expressed in all human cells studied (endothelial cells, HeLa, and HEK cells) and was down-regulated after silencing with specific siRNA. EGFP-STK35L1 was localized in the nucleus and the nucleolus. By combining syntenic and gene structure pattern data and homology searches, two further STK35L1 homologs, STK35L2 (previously known as PDIK1L) and STK35L3, were found. All these protein kinase homologs were conserved throughout the vertebrates. The STK35L3 gene was specifically lost during placental mammalian evolution. Using comparative genomics, we have identified orthologous sets of these three protein kinases genes and their possible ancestor gene in two sea squirt genomes. We found the full-length coding sequence of the STK35 gene and termed it as STK35L1. We identified a new third STK35-like gene, STK35L3, in vertebrates and a possible ancestor gene in sea squirt genome. This study will provide a comprehensive platform to explore the role of STK35L kinases in cell functions and human diseases
GOPred: GO Molecular Function Prediction by Combined Classifiers
Functional protein annotation is an important matter for in vivo and in silico biology. Several computational methods have been proposed that make use of a wide range of features such as motifs, domains, homology, structure and physicochemical properties. There is no single method that performs best in all functional classification problems because information obtained using any of these features depends on the function to be assigned to the protein. In this study, we portray a novel approach that combines different methods to better represent protein function. First, we formulated the function annotation problem as a classification problem defined on 300 different Gene Ontology (GO) terms from molecular function aspect. We presented a method to form positive and negative training examples while taking into account the directed acyclic graph (DAG) structure and evidence codes of GO. We applied three different methods and their combinations. Results show that combining different methods improves prediction accuracy in most cases. The proposed method, GOPred, is available as an online computational annotation tool (http://kinaz.fen.bilkent.edu.tr/gopred)
An analysis of reported motivational orientation in students undertaking doctoral studies in the biomedical sciences
Deposition of callose in young ovules of two Taraxacum species varying in the mode of reproduction
High-throughput quantification of more than 100 primary- and secondary-metabolites, and phytohormones by a single solid-phase extraction based sample preparation with analysis by UHPLC–HESI–MS/MS
C9orf72 Expansion Disrupts ATM-mediated Chromosomal Break Repair
A hexanucleotide repeat expansion represents the most common genetic cause of
amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the
mechanisms by which the expansion cause neurodegeneration are poorly understood. We
report elevated levels of DNA/RNA hybrids (R-loops) and double-strand breaks (DSBs) in
rodent neurons, human cells, and in C9orf72-ALS patient spinal cord tissues.
Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated
DNA repair signalling and accumulation of protein-linked DNA breaks. We further
reveal that defective ATM-mediated DNA repair is a consequence of p62 accumulation,
which impairs H2A ubiquitylation and perturbs ATM signalling. Adeno-associated virus-
mediated expression of C9orf72-related RNA and dipeptide repeats in the murine central
nervous system causes elevated DSBs, ATM defects, and triggers neurodegeneration.
These findings identify R-Loops, DSBs, and defective ATM-mediated repair as
pathological consequences of C9orf72 expansions, and suggest that C9orf72-linked
neurodegeneration is driven, at least in part, by genomic instability
Inflammatory resolution: New opportunities for drug discovery
Treatment of inflammatory diseases today is largely based on interrupting the synthesis or action
of mediators that drive the host’s response to injury. Non-steroidal anti-inflammatories, steroids
and antihistamines, for instance, were developed on this basis. Although such small-molecule
inhibitors have provided the main treatment for inflammatory arthropathies and asthma, they are
not without their shortcomings. This review offers an alternative approach to the development of
novel therapeutics based on the endogenous mediators and mechanisms that switch off acute
inflammation and bring about its resolution. It is thought that this strategy will open up new
avenues for the future management of inflammation-based diseases
DETECTION OF MISSENSE MUTATIONS BY SINGLE-STRAND CONFORMATIONAL POLYMORPHISM (SSCP) ANALYSIS IN 5 DYSFUNCTIONAL VARIANTS OF COAGULATION FACTOR-VII
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