Local Conformational Flexibility Provides a Basis for Facile Polymer Formation in Human Neuroserpin

Neuroserpin is a regulator of neuronal growth and plasticity. Like other members of the serpin family, neuroserpin undergoes a large conformational change as part of its function. Unlike other serpins such as alpha(1)-antitrypsin, wild-type neuroserpin will polymerize under near-physiological conditions, and will spontaneously transition to the latent state. To probe the origins of this conformational lability, we have performed hydrogen exchange measurements and molecular-dynamics simulations on human neuroserpin. Hydrogen exchange indicates that neuroserpin has greater flexibility in the breach region and in beta-strand 1C compared with alpha(1)-antitrypsin. Molecular-dynamics simulations show that the distance between the top of beta-strands 3 and 5A averages 4.6 angstrom but becomes as large as 7.5 angstrom in neuroserpin while it remains stable at similar to 3.5 angstrom in alpha(1)-antitrypsin. Further simulations show that the stabilizing S340A mutation suppresses these fluctuations in neuroserpin. The first principal component calculated from the simulations shows a movement of helix F away from the face of beta-sheet A in neuroserpin while no such movement is evident in alpha(1)-antitrypsin. The increased mobility of these regions in neuroserpin relative to alpha(1)-antitrypsin provides a basis for neuroserpin's increased tendency toward the formation of polymers and/or the latent state.