Effect of missense mutations on structure and interaction of anaplastic Lymphoma kinase (ALK) in neuroblastom

Neuroblastoma is a cancer of the sympathetic nervous system, accounting for upto 15% of childhood cancer mortality. It can occur in many areas but most of them begin in the abdomen in the adrenal gland and can spread to the bones and other areas. http://en.wikipedia.org/wiki/Neuroblastoma-cite_note-pmid19383347-3. Unfortunately, like other cancers, its causes are still poorly understood. Anaplastic lymphoma kinase (ALK), a membrane associated tyrosine kinase was recently found to be mutated in neuroblastoma. Protein sequence of ALK was retrieved from UniProt and the seven identified mutations were substituted in native sequence to get its mutant proteins. Significant changes were explored in the mutant secondary structures when compared with the native protein. Changes were also observed in the physiochemical properties and it can therefore be inferred that, these changes may be translated in the tertiary structures due to their effects on the folding pattern. Tertiary structure of the protein modeled after refinement and validation was submitted to Protein Model Database (PMDB) and was assigned with the PMDB ID P0077827. RMSD values of the mutant structures were observed deviated from the native structure when compared with probability < 0.05. It was observed that there are a total of 15 Disordered Regions in the protein having a total of 290 Disordered Residues. Protein-ligand interaction analysis was performed to investigate the effects of mutations damaging its interactions and it was observed that the mutations understudy affects its interactions with ATP which ultimately results in causing neuroblastoma. This study was based on the in silico mutation analysis of Seven missense mutations of anaplastic lymphoma kinase which can better explain why missense mutations in ALK protein cause neuroblastoma. Structure and sequence based computations were systematically and comprehensively evaluated applied to the mutants in anaplastic lymphoma kinase and on the basis of our observations a detailed structural explanations have been developed for the measured and predicted impact of these missense substitutions.