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.

Ricagno, S., Pezzullo, M., Barbiroli, A., Manno, M., Levantino, M., Santangelo, M.G., et al. (2010). Two latent and two hyperstable polymeric forms of human neuroserpin. BIOPHYSICAL JOURNAL, 99, 3402-3411 [10.1016/j.bpj.2010.09.021].

Two latent and two hyperstable polymeric forms of human neuroserpin

LEVANTINO, Matteo;SANTANGELO, Maria Grazia;
2010

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.
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
http://www.cell.com/biophysj/abstract/S0006-3495(10)01168-9
Ricagno, S., Pezzullo, M., Barbiroli, A., Manno, M., Levantino, M., Santangelo, M.G., et al. (2010). Two latent and two hyperstable polymeric forms of human neuroserpin. BIOPHYSICAL JOURNAL, 99, 3402-3411 [10.1016/j.bpj.2010.09.021].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/52421
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