Biophysical study of the complex formed by the cellular prion protein and the co-chaperone hop/STI-1: in search for the structural basis of its signaling properties.

SEBASTIÁN A. ROMANO; YRAIMA CORDEIRO; LUIS MAURÍCIO T. R. LIMA; DÉBORA FOGUEL; RAFAEL LINDEN

Búzios

Congreso; I IBRO/LARC Congress of Neuroscience; 2008

IBRO

Numerous studies indicate that a pathological isoform (PrPSc) of the cellular prion protein (PrPC) is the infectious agent of transmissible spongiform encephalopathies (TSEs), however, the cellular function of PrPC is still unclear. Lately, it has been shown that PrPC modulates diverse aspects of cellular processes. In particular, the recruitment of neuronal PrPc by the co-chaperone hop/STI1, induces trophic, proliferative and neuroprotective signals. Aiming to gain insight into the structural features of this interaction, we present an in vitro biophysical and structural analysis of hop/STI1 and the PrP:hop/STI1 complex. After confirming the complex formation by fluorescence anisotropy, analysis of far UV Cicular Dichroism (CD) spectra suggests that complexation triggers a significant stretching of helical structures of PrP, a mechanism that could represent a relevant structural basis for the signaling capabilities of the complex. Further evidence for a structural rearrangement of PrP was provided by intrinsic fluorescence spectroscopy. Furthermore, Small Angle X-ray Scattering (SAXS) data was collected, allowing us to obtain structural parameters and low-resolution models of hop/STI1 and PrP:hop/STI1 molecular envelopes. Previously resolved structural models of the globular domain of PrP and the tetratricopeptide repeat (TPR) domains of hop/STI1 were superimposed over the obtained models, gaining important insight into their structural organization. Importantly, these models suggest that complexation also trigger significant modifications to the hop/STI1 tertiary structure.