title: Local conformational flexibility provides a basis for facile polymer formation in human neuroserpin.
abstract: 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 α(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 β-strand 1C compared with α(1)-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 α(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 β-sheet A in neuroserpin while no such movement is evident in α(1)-antitrypsin. The increased mobility of these regions in neuroserpin relative to α(1)-antitrypsin provides a basis for neuroserpin's increased tendency toward the formation of polymers and/or the latent state.
authors.affiliation: Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Sarkar
authors.forename: Crystal
authors.initials: C
authors.lastname: Zhou
authors.forename: Robert
authors.initials: R
authors.lastname: Meklemburg
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Wintrode
mesh_terms: D020134:Catalytic Domain; D041961:Deuterium Exchange Measurement; D006801:Humans; D006860:Hydrogen Bonding; D013058:Mass Spectrometry; D056004:Molecular Dynamics Simulation; D009479:Neuropeptides / Q000737:chemistry* / Q000378:metabolism; D025341:Principal Component Analysis; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D059748:Proteolysis; D015843:Serpins / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D000097522:Neuroserpin
chemical_list: D009479:Neuropeptides; D015843:Serpins; D000097522:Neuroserpin