|Title||Structural systems biology approach delineate the functional implications of SNPs in exon junction complex interaction network.|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||M DDarshan V, Sivaramakrishnan V, K Kumar A|
|Journal||J Biomol Struct Dyn|
|Date Published||2023 Jan 08|
In eukaryotes, transcripts that carry premature termination codons (PTC) leading to truncated proteins are degraded by the Nonsense Mediated Decay (NMD) machinery. Missense and nonsense Single Nucleotide Polymorphisms (SNPs) in proteins belonging to Exon junction complex (EJC) and up-frameshift protein (UPF) will compromise NMD leading to the accumulation of truncated proteins in various diseases. The EJC and UPF which are involved in NMD is a good model system to study the effect of SNPs at a system level. Despite the availability of crystal structures, computational tools, and data on mutational and deletion studies, with functional implications, an integrated effort to understand the impact of SNPs at the systems level is lacking. To study the functional consequences of missense SNPs, sequence-based techniques like SIFT and PolyPhen which classify SNPs as deleterious or non-deleterious and structure-based methods like FoldX which calculate the Delta Delta G, (ddGs, ∆∆G) are used. Using FoldX, the ddG for mutations with experimentally validated functional effects is calculated and compared with those calculated for SNPs in the same protein-protein interaction interface. Further, a model is conceived to explain the functional implications of SNPs based on the effects observed for known mutants. The results are visualized in a network format. The effects of nonsense mutations are discerned by comparing with deletion mutation studies and loss of interaction in the crystal structure. The present work not only integrates genomics, proteomics, and classical genetics with 'Structural Biology' but also helps to integrate it into a 'systems-level functional network'. Communicated by Ramaswamy H. Sarma.
|Alternate Journal||J Biomol Struct Dyn|