title: Common structural traits across pathogenic mutants of the human prion protein and their implications for familial prion diseases.
abstract: Human (Hu) familial prion diseases are associated with about 40 point mutations of the gene coding for the prion protein (PrP). Most of the variants associated with these mutations are located in the globular domain of the protein. We performed 50 ns of molecular dynamics for each of these mutants to investigate their structure in aqueous solution. Overall, 1.6 μs of molecular dynamics data is presented. The calculations are based on the AMBER(parm99) force field, which has been shown to reproduce very accurately the structural features of the HuPrP wild type and a few variants for which experimental structural information is available. The variants present structural determinants different from those of wild-type HuPrP and the protective mutation HuPrP(E219K-129M). These include the loss of salt bridges in α(2)-α(3) regions and the loss of π-stacking interactions in the β(2)-α(2) loop. In addition, in the majority of the mutants, the α(3) helix is more flexible and Y169 is more solvent exposed. The presence of similar traits in this large spectrum of mutations hints to a role of these fingerprints in their known disease-causing properties. Overall, the regions most affected by disease-linked mutations in terms of structure and/or flexibility are those involved in the pathogenic conversion to the scrapie form of the protein and in the interaction with cellular partners. These regions thus emerge as optimal targets for antibody- and ligand-binding studies.
authors.affiliation: Statistical and Biological Physics Sector, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Via Bonomea 265, I-34136 Trieste, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Cong
authors.forename: Rocco
authors.initials: R
authors.lastname: Caliandro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics*; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D017510:Protein Folding; D020033:Protein Isoforms; D013329:Structure-Activity Relationship
chemical_list: C512656:PRNP protein, human; D018621:PrPC Proteins; D018620:PrPSc Proteins; D000072002:Prion Proteins; D011328:Prions; D020033:Protein Isoforms