Hypothesis-free phenotype prediction within a genetics-first framework.

Cohort-wide sequencing studies have revealed that the largest category of variants is those deemed 'rare', even for the subset located in coding regions (99% of known coding variants are seen in less than 1% of the population. Associative methods give some understanding how rare genetic variants influence disease and organism-level phenotypes. But here we show that additional discoveries can be made through a knowledge-based approach using protein domains and ontologies (function and phenotype) that considers all coding variants regardless of allele frequency.

Recognition of sites of functional specialisation in all known eukaryotic protein kinase families.

The conserved function of protein phosphorylation, catalysed by members of protein kinase superfamily, is regulated in different ways in different kinase families. Further, differences in activating triggers, cellular localisation, domain architecture and substrate specificity between kinase families are also well known. While the transfer of γ-phosphate from ATP to the hydroxyl group of Ser/Thr/Tyr is mediated by a conserved Asp, the characteristic functional and regulatory sites are specialized at the level of families or sub-families.

Interaction of the Saccharomyces cerevisiae RING-domain protein Nse1 with Nse3 and the Smc5/6 complex is required for chromosome replication and stability.

Genomic stability is maintained by the concerted actions of numerous protein complexes that participate in chromosomal duplication, repair, and segregation. The Smc5/6 complex is an essential multi-subunit complex crucial for repair of DNA double-strand breaks. Two of its subunits, Nse1 and Nse3, are homologous to the RING-MAGE complexes recently described in human cells.

Sendai virus recruits cellular villin to remodel actin cytoskeleton during fusion with hepatocytes.

Reconstituted Sendai viral envelopes (virosomes) are well recognized for their promising potential in membrane fusion-mediated delivery of bioactive molecules to liver cells. Despite the known function of viral envelope glycoproteins in catalyzing fusion with cellular membrane, the role of host cell proteins remains elusive. Here, we used two-dimensional differential in-gel electrophoresis to analyze hepatic cells in early response to virosome-induced membrane fusion.

Conservation of structural fluctuations in homologous protein kinases and its implications on functional sites.

Our aim is to explore the similarities in structural fluctuations of homologous kinases. Gaussian Network Model based Normal Mode Analysis was performed on 73 active conformation structures in Ser/Thr/Tyr kinase superfamily. Categories of kinases with progressive evolutionary divergence, viz.

A Gaussian network model study suggests that structural fluctuations are higher for inactive states than active states of protein kinases.

We performed Gaussian network model based normal mode analysis of 3-dimensional structures of multiple active and inactive forms of protein kinases. In 14 different kinases, a more number of residues (1095) show higher structural fluctuations in inactive states than those in active states (525), suggesting that, in general, mobility of inactive states is higher than active states. This statistically significant difference is consistent with higher crystallographic B-factors and conformational energies for inactive than active states, suggesting lower stability of inactive forms.