Dynamic Structure of NGF and proNGF Complexed with p75NTR: Pro-Peptide Effect

• Type: Article in International Scientific Journal
• Date: 2014

Authors

António Pimenta (Author) Other; Daniel Dourado (Author) Other; João Martins (Author) Other; André Melo (Author) FCUP; Maria Natália Cordeiro (Author) FCUP; Ramiro D Almeida (Author) Other; Giulia Morra (Author) Other; Irina Moreira (Author) Other

Journal

Title: Journal of Chemical Information and Modeling

Vol. 54

Pages: 2051-2067

ISSN: 1549-9596

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 5 Citations

ISI Web of Science

Scopus - 5 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

CORDIS: Physical sciences > Chemistry

Other information

Authenticus ID: P-009-PWT

DOI: 10.1021/ci500101n

Abstract (EN): Crystallographic structures of NGF/p75NTR and proNGF/p75NTR were previously obtained in 2:1 and 2:2 stoichiometries, respectively. However, evidence shows that both stoichiometries can occur for mature neurotrophins and proneurotrophins. We used Molecular Dynamics (MD) simulations to examine the energetic and structural characteristics of these two complete systems as well as the uncomplexed forms of NGF and understand how these could translate in a new view of different biological outcomes. Here, we show that one chain at the 2:2 proNGF complex seems to be preferentially lost creating a 2:1 structure able to interact with sortilin. We also demonstrated that the structure of the neurotrophin dimers is not pre-established and suffers large structural modifications upon p75NTR binding. Moreover, our data suggests an elegant explanation for the dual role of NGF in neuronal cell death and survival, where different stoichiometries induce conformational changes that might be the basis for the different biological outcomes observed with the mature and proforms of neurotrophins.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17