Two latent and two hyperstable polymeric forms of human neuroserpin

Matteo Levantino, Maria Grazia Santangelo, Alberto Barbiroli, Stefano Ricagno, Francesco Bonomi, Mauro Manno, Martino Bolognesi, Margherita Pezzullo

Risultato della ricerca: Article

14 Citazioni (Scopus)

Abstract

Human neuroserpin (hNS) is a serine protease inhibitor that belongs to the serpin superfamily and is expressed in nervous tissues. The serpin fold is generally characterized by a long exposed loop, termed the reactive center loop, that acts as bait for the target protease. Intramolecular insertion of the reactive center loop into the main serpin β-sheet leads to the serpin latent form. As with other known serpins, hNS pathological mutants have been shown to accumulate as polymers composed of quasi-native protein molecules. Although hNS polymerization has been intensely studied, a general agreement about serpin polymer organization is still lacking. Here we report a biophysical characterization of native hNS that is shown to undergo two distinct conformational transitions, at 55°C and 85°C, both leading to distinct latent and polymeric species. The latent and polymer hNS forms obtained at 45°C and 85°C differ in their chemical and thermal stabilities; furthermore, the hNS polymers also differ in size and morphology. Finally, the 85°C polymer shows a higher content of intermolecular β-sheet interactions than the 45°C polymer. Together, these results suggest a more complex conformational scenario than was previously envisioned, and, in a general context, may help reconcile the current contrasting views on serpin polymerization.
Lingua originaleEnglish
pagine (da-a)3402-3411
Numero di pagine10
RivistaBiophysical Journal
Volume99
Stato di pubblicazionePublished - 2010

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Serpins
Polymers
Polymerization
Nerve Tissue
Serine Proteinase Inhibitors
neuroserpin
Peptide Hydrolases
Hot Temperature

All Science Journal Classification (ASJC) codes

  • Biophysics

Cita questo

Levantino, M., Santangelo, M. G., Barbiroli, A., Ricagno, S., Bonomi, F., Manno, M., ... Pezzullo, M. (2010). Two latent and two hyperstable polymeric forms of human neuroserpin. Biophysical Journal, 99, 3402-3411.

Two latent and two hyperstable polymeric forms of human neuroserpin. / Levantino, Matteo; Santangelo, Maria Grazia; Barbiroli, Alberto; Ricagno, Stefano; Bonomi, Francesco; Manno, Mauro; Bolognesi, Martino; Pezzullo, Margherita.

In: Biophysical Journal, Vol. 99, 2010, pag. 3402-3411.

Risultato della ricerca: Article

Levantino, M, Santangelo, MG, Barbiroli, A, Ricagno, S, Bonomi, F, Manno, M, Bolognesi, M & Pezzullo, M 2010, 'Two latent and two hyperstable polymeric forms of human neuroserpin', Biophysical Journal, vol. 99, pagg. 3402-3411.
Levantino M, Santangelo MG, Barbiroli A, Ricagno S, Bonomi F, Manno M e altri. Two latent and two hyperstable polymeric forms of human neuroserpin. Biophysical Journal. 2010;99:3402-3411.
Levantino, Matteo ; Santangelo, Maria Grazia ; Barbiroli, Alberto ; Ricagno, Stefano ; Bonomi, Francesco ; Manno, Mauro ; Bolognesi, Martino ; Pezzullo, Margherita. / Two latent and two hyperstable polymeric forms of human neuroserpin. In: Biophysical Journal. 2010 ; Vol. 99. pagg. 3402-3411.
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AU - Levantino, Matteo

AU - Santangelo, Maria Grazia

AU - Barbiroli, Alberto

AU - Ricagno, Stefano

AU - Bonomi, Francesco

AU - Manno, Mauro

AU - Bolognesi, Martino

AU - Pezzullo, Margherita

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N2 - Human neuroserpin (hNS) is a serine protease inhibitor that belongs to the serpin superfamily and is expressed in nervous tissues. The serpin fold is generally characterized by a long exposed loop, termed the reactive center loop, that acts as bait for the target protease. Intramolecular insertion of the reactive center loop into the main serpin β-sheet leads to the serpin latent form. As with other known serpins, hNS pathological mutants have been shown to accumulate as polymers composed of quasi-native protein molecules. Although hNS polymerization has been intensely studied, a general agreement about serpin polymer organization is still lacking. Here we report a biophysical characterization of native hNS that is shown to undergo two distinct conformational transitions, at 55°C and 85°C, both leading to distinct latent and polymeric species. The latent and polymer hNS forms obtained at 45°C and 85°C differ in their chemical and thermal stabilities; furthermore, the hNS polymers also differ in size and morphology. Finally, the 85°C polymer shows a higher content of intermolecular β-sheet interactions than the 45°C polymer. Together, these results suggest a more complex conformational scenario than was previously envisioned, and, in a general context, may help reconcile the current contrasting views on serpin polymerization.

AB - Human neuroserpin (hNS) is a serine protease inhibitor that belongs to the serpin superfamily and is expressed in nervous tissues. The serpin fold is generally characterized by a long exposed loop, termed the reactive center loop, that acts as bait for the target protease. Intramolecular insertion of the reactive center loop into the main serpin β-sheet leads to the serpin latent form. As with other known serpins, hNS pathological mutants have been shown to accumulate as polymers composed of quasi-native protein molecules. Although hNS polymerization has been intensely studied, a general agreement about serpin polymer organization is still lacking. Here we report a biophysical characterization of native hNS that is shown to undergo two distinct conformational transitions, at 55°C and 85°C, both leading to distinct latent and polymeric species. The latent and polymer hNS forms obtained at 45°C and 85°C differ in their chemical and thermal stabilities; furthermore, the hNS polymers also differ in size and morphology. Finally, the 85°C polymer shows a higher content of intermolecular β-sheet interactions than the 45°C polymer. Together, these results suggest a more complex conformational scenario than was previously envisioned, and, in a general context, may help reconcile the current contrasting views on serpin polymerization.

KW - serpins; human neuroserpin; latent neuroserpin; pathological serpin aggregation; serpinopathies; FENIB

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