Naslov
Structural Rearrangements at Physiological pH : Nuclear Magnetic Resonance Insights from the V210I Human Prion Protein Mutant

Autori
Biljan, Ivana ; Ilc, Gregor ; Giachin, Gabriele ; Plavec, Janez ; Legname, Giuseppe

Izvornik
Biochemistry (Easton) (0006-2960) 51 (2012), 38; 7465-7474

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

Ključne riječi
pPrions; transmissible spongiform encephalopathies; Familial Creutzfeldt–Jakob disease; pH; NMR structure determination
(prions; transmissible spongiform encephalopathies; Familial Creutzfeldt–Jakob disease; pH; NMR structure determination)

Sažetak
A major focus in prion structural biology studies is unraveling the molecular mechanism leading to the structural conversion of PrPC to its pathological form PrPSc. In our recent studies, we attempted to understand the early events of the conformational changes leading to PrPSc using as investigative tools point mutations clustered in the open reading frame of the human PrP gene (PRNP) and linked to genetic forms of human prion diseases. In the present work, we investigate the effect of pH on the NMR structure of recombinant human PrP (HuPrP) carrying the pathological V210I mutation responsible for familial Creutzfeldt– Jakob disease. The NMR structure of HuPrP(V210I) determined at pH 7.2 shows the same overall fold as previously solved structure of HuPrP(V210I) at pH 5.5. It consists of a disordered N-terminal tail (residues 90-124) and a globular C-terminal domain (residues 125-231) comprising three α- helices and short antiparallel β-sheet. Detailed comparison of 3D structures of HuPrP(V210I) at pH 7.2 and 5.5 revealed significant local structural differences with the most prominent pH-related structural variations clustered in the a2-a3 interhelical region, at the interface of b1-a1 loop, helices a1 and a3, and in the b2-a2 loop region. The detailed analysis of interactions amongst secondary structure elements suggests a higher structural ordering of HuPrP(V210I) under neutral pH conditions thus implying that spontaneous misfolding of PrPC may occur under acidic pH conditions in endosomal compartments.

Izvorni jezik
Engleski

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