Reciprocal remodeling upon binding of the prion protein to its signaling partner hop/STI1

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

FASEB JOURNAL

FEDERATION AMER SOC EXP BIOL

Lugar: Bethesda; Año: 2009 vol. 23 p. 4308 - 4316

0892-6638

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. Using recombinant wild-type and mutant mouse proteins and binding peptides, we measured circular dichroism (CD), fluorescence spectroscopy, and small angle X-ray scattering (SAXS). PrPC:hop/STI1 interaction triggers loss of PrP helical structures, involving at least a perturbation of the PrP143-153 alpha-helix, but no secondary structural modification of hop/STI1 was detected. Novel SAXS models revealed a significant C-terminal compaction of hop/STI1 when bound to PrP. 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 PrP143-153 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 of PrPC-dependent multiprotein signaling complexes.