Reciprocal remodeling upon binding of the prion protein to its signaling partner hop/STI1.
The glycosylphosphatidylinositol (GPI)-anchored prion protein (PrP(C)), usually associated with neurodegenerative diseases, modulates various cellular responses and may scaffold multiprotein cell surface signaling complexes. Engagement of PrP(C) with the secretable cochaperone hop/STI1 induces neurotrophic transmembrane signals through unknown molecular mechanisms. We addressed whether interaction of PrP(C) 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). PrP(C):hop/STI1 interaction triggers loss of PrP helical structures, involving at least a perturbation of the PrP(143-153) 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 PrP(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 PrP(C), 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 PrP(C):hop/STI1 interaction, consistent with the hypothesis of PrP(C)-dependent multiprotein signaling complexes.
Romano
Sebastián A
SA
Instituto de Biofísica da UFRJ, CCS, Bloco G, Cidade Universitária, RJ 21941-902, Brazil.
Cordeiro
Yraima
Y
Lima
Luis Maurício T R
LM
Lopes
Marilene H
MH
Silva
Jerson L
JL
Foguel
Débora
D
Linden
Rafael
R
D000818:Animals; D006360:Heat-Shock Proteins / Q000378:metabolism*; D051379:Mice; D008967:Molecular Biology; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence
D006360:Heat-Shock Proteins; D011328:Prions; C489791:Stip1 protein, mouse