Title : Molecular and structural insight into pro
NGF engagement of
p75NTR and
sortilin
Abstract :
- Nerve growth factor ( NGF ) is initially synthesized as a precursor , pro NGF , that is cleaved to release its C-terminal mature form
- Recent studies suggested that pro NGF is not an inactive precursor but acts as a signaling ligand distinct from its mature counterpart
- pro NGF and mature NGF initiate opposing biological responses by utilizing both distinct and shared receptor components
- In this study, we carried out structural and biochemical characterization of pro NGF interactions with p75NTR and sortilin
- We crystallized pro NGF complexed to p75NTR and present the structure at 3 .75-A resolution
- The structure reveals a 2:2 symmetric binding mode, as compared with the asymmetric structure of a previously reported crystal structure of mature NGF complexed to p75NTR and the 2:2 symmetric complex of neurotrophin-3 ( NT-3 ) and p75NTR
- Here, we discuss the possible origins and implications of the different stoichiometries
- In the pro NGF- p75NTR complex, the pro regions of pro NGF are mostly disordered and two hairpin loops (loop 2) at the top of the NGF dimer have undergone conformational changes in comparison with mature NT structures, suggesting possible interactions with the propeptide
- We further explored the binding characteristics of pro NGF to sortilin using surface plasmon resonance and cell-based assays and determined that calcium ions promote the formation of a stable ternary complex of pro NGF- sortilin- p75NTR
- These results, together with those of previous structural and mechanistic studies of NT- receptor interactions, suggest the potential for distinct signaling activities through p75NTR mediated by different NT- induced conformational changes
Output (sent_index, trigger,
protein,
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Output(Part-Of) (sent_index,
protein,
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*Output_Site_Fusion* (sent_index,
protein,
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site):