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

• Published in: Biophysical journal 2011-10, Vol.101 (7), p.1758-1765
• Main Authors: Sarkar, Anindya, Zhou, Crystal, Meklemburg, Robert, Wintrode, Patrick L.
• Format: Article
• Language: English
• Subjects: Catalytic Domain; Deuterium Exchange Measurement; Flexibility; Fluctuation; Human; Humans; Hydrogen; Hydrogen Bonding; Mass Spectrometry; Mathematical analysis; Molecular dynamics; Molecular Dynamics Simulation; Movement; Mutation; Neuropeptides - chemistry; Neuropeptides - metabolism; Neuroserpin; polymerization; Polymers; Principal Component Analysis; Protein; Protein Multimerization; Protein Structure, Quaternary; Protein Structure, Secondary; Proteins; Proteolysis; Regulators; Serpins - chemistry; Serpins - metabolism; Simulation; Thermodynamics
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2011.08.037

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 α1-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 β-strand 1C compared with α1-antitrypsin. Molecular-dynamics simulations show that the distance between the top of β-strands 3 and 5A averages 4.6 Å but becomes as large as 7.5 Å in neuroserpin while it remains stable at ∼3.5 Å in α1-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 β-sheet A in neuroserpin while no such movement is evident in α1-antitrypsin. The increased mobility of these regions in neuroserpin relative to α1-antitrypsin provides a basis for neuroserpin's increased tendency toward the formation of polymers and/or the latent state.