Naslov
Toward the molecular basis of inherited prion diseases : NMR structure of the human prion protein with V210I mutation

Autori
Biljan, Ivana ; Ilc, Gregor ; Giachin, Gabriele ; Raspadori, Andrea ; Zhukov, Igor ; Plavec, Janez ; Legname, Giuseppe

Izvornik
Journal of molecular biology (0022-2836) 412 (2011), 4; 660-673

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
prions; mutants; transmissible spongiform encephalopathies; genetic Creutzfeldt-Jakob disease; NMR structure determination

Sažetak
The development of transmissible spongiphorm encephalopathies (TSE) is associated with the conversion of the cellular prion protein (PrPC) into the misfolded, pathogenic isoform (PrPSc). Spontaneous generation of PrPSc in inherited forms of disease is caused by mutations in gene coding for PrP (PRNP). In this work, we describe the NMR solution-state structure of the truncated recombinant human (Hu) PrP carrying the pathological V210I mutation linked to genetic Creutzfeldt-Jakob disease (CJD). The three-dimensional structure of V210I mutant consists of unstructured N-terminal part (residues 90-124) and well-defined C-terminal domain (residues 125-228). The C-terminal domain contains three a-helices (residues 144-156, 170-194 and 200-228) and a short, antiparallel b-sheet (residues 129-130 and 162-163). Comparison with the structure of the WT HuPrP revealed that, although two structures share similar global architecture, mutation introduces some local structural differences. The observed variations are mostly clustered in a2-a3 inter-helical interface and in the b2-a2 loop region. Introduction of bulkier Ile at position 210 induces reorientations of several residues that are part of hydrophobic core thus influencing a2-a3 inter-helical interactions. Another important structural feature involves the alteration of conformation of the b2–a2 loop region and the subsequent exposure of hydrophobic cluster to solvent which facilitates intermolecular interactions involved in spontaneous generation of PrPSc. The NMR structure of V210I mutant offers new clues about the earliest events of the pathogenic conversion process and could be used for the development of antiprion drugs.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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