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Biophys J. 2011 Oct 5;101(7):1758-65. doi: 10.1016/j.bpj.2011.08.037.

Local conformational flexibility provides a basis for facile polymer formation in human neuroserpin.

Author information

1
Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, Ohio, USA.

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.

PMID:
21961602
PMCID:
PMC3183757
DOI:
10.1016/j.bpj.2011.08.037
[Indexed for MEDLINE]
Free PMC Article

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