Investigating co-evolution of functionally associated phosphosites in human.

Phosphorylation is essential for protein function and signal transduction in eukaryotic cells. With the rapid development of mass spectrometry technology, a large number of phosphosites are identified. However, high-throughput methods of functional characterization for phosphosites are still scarce. In this study, we inspected if the co-evolution property can be used as an indicator to explore function of phosphosites through investigating co-evolutionary relationship between functionally associated phosphosites in human. In practice, the evolution attributes of phosphosites were represented with phylogenetic profiles, and then co-evolutionary correlations of functionally associated phosphosites were detected on three levels: (1) phosphosites within one protein; (2) phosphosites in different proteins participating in the same signal transduction pathways, and (3) general phosphosites. Results of the detection show that co-evolution is a general property of functionally associated phosphosites. This finding suggests to some degree that it is feasible to use the co-evolution property in exploring the function of phosphosites and investigating the functional association between them.

The de novo sequence origin of two long non-coding genes from an inter-genic region.

BACKGROUND: The gene Polymorphic derived intron-containing, known as Pldi, is a long non-coding RNA (lncRNA) first discovered in mouse. Although parts of its sequence were reported to be conserved in rat and human, it can only be expressed in mouse testis with a mouse-specific transcription start site. The consensus sequence of Pldi is also part of an antisense transcript AK158810 expressed in a wide range of mouse tissues. RESULT: We focused on sequence origin of Pldi and Ak158810. We demonstrated that their sequence was originated from an inter-genic region and is only presented in mammalians. Transposable events and chromosome rearrangements were involved in the evolution of ancestral sequence. Moreover, we discovered high conservation in part of this region was correlated with chromosome rearrangements, CpG demethylation and transcriptional factor binding motif. These results demonstrated that multiple factors contributed to the sequence origin of Pldi. CONCLUSIONS: We comprehensively analyzed the sequence origin of Pldi-Ak158810 loci. We provided various factors, including rearrangement, transposable elements, contributed to the formation of the sequence.

Impact of peripheral mutations on the access channels of human cytochrome P450 1A2.

Communicated by Ramaswamy H. Sarma.

Computational Study of HCV p7 Channel: Insight into a New Strategy for HCV Inhibitor Design.

HCV p7 protein is a cation-selective ion channel, playing an essential role during the life cycle of HCV viruses. To understand the cation-selective mechanism, we constructed a hexameric model in lipid bilayers of HCV p7 protein for HCB JFH-1 strain, genotype 2a. In this structural model, His9 and Val6 were key factors for the HCV cation-selective ion channel. The histidine residues at position 9 in the hexameric model formed a first gate for HCV p7 channel, acting as a selectivity filter for cations. The valines mentioned above formed a second gate for HCV p7 channel, serving as a hydrophobic filter for the dehydrated cations. The binding pocket for the channel blockers, e.g., amantadine and rimantadine, was composed of residues 20-26 in H2 helix and 52-60 in H3 helix in i + 2 monomer. However, the molecular volumes for both amantadine and rimantadine were too small for the binding pocket of HCV p7 channel. Thus, designing a compound similar with rimantadine and having much larger volume would be an effective strategy for discovering inhibitors against HCV p7 channel. To achieve this point, we used rimantadine as a structural template to search ChEMBL database for the candidates employing favorable binding affinities to HCV p7 channel. As a result, six candidates were identified to have potential to be novel inhibitors against HCV p7 channel.

An examination of the OMIM database for associating mutation to a consensus reference sequence.

Gene mutation (e.g. substitution, insertion and deletion) and related phenotype information are important biomedical knowledge. Many biomedical databases (e.g. OMIM) incorporate such data. However, few studies have examined the quality of this data. In the current study, we examined the quality of protein single-point mutations in the OMIM and identified whether the corresponding reference sequences align with the mutation positions. Our results show that close to 20% of mutation data cannot be mapped to a single reference sequence. The failed mappings are caused by position conflict, site shifting (peptide, N-terminal methionine) and other types of data error. We propose a preliminary model to resolve such inconsistency in the OMIM database.