6533b856fe1ef96bd12b2254

RESEARCH PRODUCT

Functional and dysfunctional isoforms of human neuroserpin

subject

description

Neuroserpin (NS) is a serine protease inhibitor (SERPIN) involved in different neurological pathologies, including the Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB), related to the aberrant polymerization of NS mutants. Here we present an in vitro and in silico characterization of native NS and its dysfunctional conformation isoforms: the proteolytically cleaved conformer, the inactive latent conformer, and the polymeric conformer. Using circular dichroism and fluorescence spectroscopy, we present an experimental validation of the latent model and highlight the main structural features of the different conformers. In par- ticular, emission spectra of aromatic residues yield a distinct conformational fingerprint, that provides a novel and simple spectroscopic tool for selecting serpin conformers in vitro. Based on the analogy between cleaved and latent serpins, we propose a structural model for latent neuroserpin, for which an experimental crystallographic structure is lacking. Molecular Dynamics simulations suggest that NS conformational stability and flexibility arise from the spatial pattern of intramolecular salt-bridges and hydrogen bonds.