title: Structural insight with mutational impact on tyrosinase and PKC-β interaction from Homo sapiens: Molecular modeling and docking studies for melanogenesis, albinism and increased risk for melanoma.
abstract: Human tyrosinase, is an important protein for biosynthetic pathway of melanin. It was studied to be phosphorylated and activated by protein kinase-C, β-subunit (PKC-β) through earlier experimentations with in vivo evidences. Documentation documents that mutation in two essentially vital serine residues in C-terminal end of tyrosinase leads to albinism. Due to the deficiency of protective shield like enzyme; melanin, albinos are at an increased peril for melanoma and other skin cancers. So, computational and residue-level insight including a mutational exploration with evolutionary importance into this mechanism lies obligatory for future pathological and therapeutic developments. Therefore, functional tertiary models of the relevant proteins were analyzed after satisfying their stereo-chemical features. Evolutionarily paramount residues for the activation of tyrosinase were perceived via multiple sequence alignment phenomena. Mutant-type tyrosinase protein (S98A and S102A) was thereby modeled, maintaining the wild-type proteins' functionality. Furthermore, this present comparative study discloses the variation in the stable residual participation (for mutant-type and wild-type tyrosinase-PKCβ complex). Mainly, an increased number of polar negatively charged residues from the wild-type tyrosinase participated with PKC-β, predominantly. Fascinatingly supported by evaluation of statistical significances, mutation even led to a destabilizing impact in tyrosinase accompanied by conformational switches with a helix-to-coil transition in the mutated protein. Even the allosteric sites in the protein got poorly hampered upon mutation leading to weaker tendency for binding partners to interact.
authors.affiliation: Department of Biotechnology, National Institute of Technology, Mahatma Gandhi Avenue, Durgapur, West Bengal, India. Electronic address: arundhati.92star@gmail.com.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, Nadia, India. Electronic address: raysujay@gmail.com.
authors.forename: Sujay
authors.initials: S
authors.lastname: Ray
mesh_terms: D000417:Albinism / Q000235:genetics*; D000495:Allosteric Site; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D062105:Molecular Docking Simulation; D014442:Monophenol Monooxygenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D064546:Protein Kinase C beta / Q000737:chemistry* / Q000378:metabolism
chemical_list: D014442:Monophenol Monooxygenase; D064546:Protein Kinase C beta
keywords: Docked protein-protein interaction and biostatistics; Melanogenesis; Molecular modeling; Multiple sequence alignment; Mutational impact