title: Checking the conformational stability of cystatin C and its L68Q variant by molecular dynamics studies: why is the L68Q variant amyloidogenic?
abstract: Human L68Q cystatin C is one of the known human amyloidogenic proteins. In its native state it is a monomer with alpha/beta structure. Experimental evidence suggests that L68Q variant associates into dimeric intermediates and that the dimers subsequently self-assemble to form amyloid deposits and insoluble fibrils. Details of the pathway of L68Q mutant amyloid formation are unclear; however, different experimental approaches with resolutions at molecular level have provided some clues. Probably, the stability and flexibility of monomeric L68Q variant play essential roles in the early steps of amyloid formation; thus, it is necessary to characterize early conformational changes of L68Q cystatin C monomers. In this paper, we demonstrate the possibility that the differences between the monomeric forms of wild-type (wt) cystatin C and its L68Q variant are responsible for higher tendency of the L68Q cystatin C amyloidogenesis. We started our studies with the simulations of wt and L68Q cystatin C monomers. Nanosecond time scale molecular dynamics simulations at 308K were performed using AMBER7.0 program. The results show that the structure of the L68Q monomer was changed, relative to the wt cystatin C structure. The results support earlier speculation that the L68Q point mutation would easily lead to dimer formation.
authors.affiliation: Faculty of Chemistry, University of Gdańsk, J. Sobieskiego 18, 80-952 Gdańsk, Poland. sylwia@chem.univ.gda.pl
authors.forename: Sylwia
authors.initials: S
authors.lastname: Rodziewicz-Motowidło
authors.forename: Maria
authors.initials: M
authors.lastname: Wahlbom
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Justyna
authors.initials: J
authors.lastname: Lagiewka
authors.forename: Robert
authors.initials: R
authors.lastname: Janowski
authors.forename: Mariusz
authors.initials: M
authors.lastname: Jaskólski
authors.forename: Anders
authors.initials: A
authors.lastname: Grubb
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Grzonka
mesh_terms: D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry*; D003198:Computer Simulation; D055316:Cystatin C; D015891:Cystatins / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D017354:Point Mutation; D011487:Protein Conformation; D012492:Salts / Q000737:chemistry; D012997:Solvents / Q000737:chemistry
chemical_list: D000682:Amyloid; C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D012492:Salts; D012997:Solvents