Mechanisms of Loss of Functions of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis 英文参考文献.docVIP

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Mechanisms of Loss of Functions of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis 英文参考文献.doc

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Mechanisms of Loss of Functions of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis 英文参考文献

MechanismsofLossofFunctionsofHumanAngiogenin VariantsImplicatedinAmyotrophicLateralSclerosis AdityaK.Padhi1,HirdeshKumar1,SuhasV.Vasaikar1,BhyravabhotlaJayaram1,2,3,JamesGomes1* 1SchoolofBiologicalSciences,IndianInstituteofTechnologyDelhi,HauzKhas,NewDelhi,India,2DepartmentofChemistry,IndianInstituteofTechnologyDelhi,Hauz Khas,NewDelhi,India,3SupercomputingFacilityforBioinformaticsandComputationalBiology,IndianInstituteofTechnologyDelhi,HauzKhas,NewDelhi,India Abstract Background: Mutations in the coding region of angiogenin (ANG) gene have been found in patients suffering from AmyotrophicLateralSclerosis(ALS).NeurodegenerationresultsfromthelossofangiogenicabilityofANG(proteincodedby ANG).Inthiswork,weperformedextensivemoleculardynamics(MD)simulationsofwild-typeANGanddiseaseassociated ANG variants to elucidate the mechanism behind the loss of ribonucleolytic activity and nuclear translocation activity, functionsneededforangiogenesis. Methodology/PrincipalFindings:MDsimulationswerecarriedouttostudythestructuralanddynamicdifferencesinthe catalytic site and nuclear localization signal residues between WT-ANG (Wild-type ANG) and six mutants. Variants K17I, S28N, P112L and V113I have confirmed association with ALS, while T195C and A238G single nucleotide polymorphisms (SNPs) encoding L35P and K60E mutants respectively, have not been associated with ALS. Our results show that loss of ribonucleolytic activity in K17I is caused by conformational switching of the catalytic residue His114 by 99u. The loss of 31 33 thatresultin nucleartranslocationactivityofS28NandP112Liscausedbychangesinthefoldingoftheresidues RRR thereductioninsolventaccessiblesurfacearea(SASA).Consequently,wepredictthatV113Iwillexhibitlossofangiogenic propertiesbylossofnucleartranslocationactivityandL35Pbylossofbothribonucleolyticactivityandnucleartranslocation activity.NofunctionallosswasinferredforK60E.TheMDsimulationresultsweresupportedbyhydrogenbondinteraction analysesandmoleculardockingstudies. Concl