Structural insights into the interaction between prion protein and nucleic acid.
The infectious agent of transmissible spongiform encephalopathies (TSE) is believed to comprise, at least in part, the prion protein (PrP). Other molecules can modulate the conversion of the normal PrP(C) into the pathological conformer (PrP(Sc)), but the identity and mechanisms of action of the key physiological factors remain unclear. PrP can bind to nucleic acids with relatively high affinity. Here, we report small-angle X-ray scattering (SAXS) and nuclear magnetic resonance spectroscopy measurements of the tight complex of PrP with an 18 bp DNA sequence. This double-stranded DNA sequence (E2DBS) binds with nanomolar affinity to the full-length recombinant mouse PrP. The SAXS data show that formation of the rPrP-DNA complex leads to larger values of the maximum dimension and radius of gyration. In addition, the SAXS studies reveal that the globular domain of PrP participates importantly in the formation of the complex. The changes in NMR HSQC spectra were clustered in two major regions: one in the disordered portion of the PrP and the other in the globular domain. Although interaction is mediated mainly through the PrP globular domain, the unstructured region is also recruited to the complex. This visualization of the complex provides insight into how oligonucleotides bind to PrP and opens new avenues to the design of compounds against prion diseases.
Lima
Luis Maurício T R
LM
Faculdade de Farmacia, Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro, RJ Brazil.
Cordeiro
Yraima
Y
Tinoco
Luzineide W
LW
Marques
Adriana F
AF
Oliveira
Cristiano L P
CL
Sampath
Srisailam
S
Kodali
Ravindra
R
Choi
Gildon
G
Foguel
Débora
D
Torriani
Iris
I
Caughey
Byron
B
Silva
Jerson L
JL
D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D006224:Cricetinae; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D008647:Mesocricetus; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D009841:Oligonucleotides / Q000737:chemistry* / Q000378:metabolism*; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012542:Scattering, Radiation; D014965:X-Rays
D001426:Bacterial Proteins; D009841:Oligonucleotides; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D011994:Recombinant Proteins; D004247:DNA