Uncovering molecular structural mechanisms of signaling mediated by the prion protein

SEBASTIÁN A. ROMANO; YRAIMA CORDEIRO; LUIS MAURÍCIO T. R. LIMA; MARILENE H. LOPES; JERSON L. SILVA; DÉBORA FOGUEL; RAFAEL LINDEN

Activity Report LNLS

Cubo

Lugar: São Carlos; Año: 2010 p. 30 - 36

1518-0204

The glycosylphosphatidylinositol (GPI)-anchored prion protein (PrPC), usually associated with neurodegenerative diseases, modulates various cellular responses and may scaffold multiprotein cell surface signaling complexes. Engagement of PrPC with the secretable cochaperone hop/STI1 induces neurotrophic transmembrane signals through unknown molecular mechanisms. We addressed whether interaction of PrPC and hop/STI1 entails structural rearrangements relevant for signaling. Circular dichroism and fluorescence spectroscopy showed that PrPC:hop/STI1 interaction triggers loss of PrP helical structures, involving at least a perturbation of the PrPC 143-153 alpha-helix. Novel SAXS models revealed a significant C-terminal compaction of hop/STI1 when bound to PrPC. Differing from a recent dimeric model of human hop/STI1, both size exclusion chromatography and SAXS data support a monomeric form of free murine hop/STI1. Changes in the PrPC 143-153 alpha-helix may engage the transmembrane signaling proteins laminin receptor precursor and neural cell adhesion molecule, both of which bind that domain of PrPC, and further ligands may be engaged by the tertiary structural changes of hop/STI1. These reciprocal structural modifications indicate a versatile mechanism for signaling mediated by PrPC:hop/STI1 interaction, consistent with the hypothesis that PrPC scaffolds multiprotein signaling complexes at the cell surface.