The tempered polymerization of human neuroserpin

• Published in: PloS one 2012-03, Vol.7 (3), p.e32444-e32444
• Main Authors: Noto, Rosina, Santangelo, Maria Grazia, Ricagno, Stefano, Mangione, Maria Rosalia, Levantino, Matteo, Pezzullo, Margherita, Martorana, Vincenzo, Cupane, Antonio, Bolognesi, Martino, Manno, Mauro
• Format: Article
• Language: English
• Subjects: Aberration; Addition polymerization; Agglomeration; Alcohol; Alzheimer's disease; Alzheimers disease; Amyloid; Biochemistry; Biology; Biophysics; Biotechnology; Councils; Deactivation; Employment; Encephalopathy; Fibrillation; Fragmentation; Genotype & phenotype; High temperature; High temperatures; Humans; Inactivation; Inclusion bodies; Inverse problems; Ischemia; Kinetics; Models, Molecular; Monomers; Mutants; Mutation; Neurodegenerative diseases; Neuropeptides - chemistry; Neuroserpin; Physics; Polymerization; Polymers; Protein Folding; Protein Multimerization - physiology; Proteins; Proteolysis; Serpins - chemistry; Studies; Synchronism; Synchronization; Temperature; Temperature range; Thermal stress
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0032444

Neuroserpin, a member of the serpin protein superfamily, is an inhibitor of proteolytic activity that is involved in pathologies such as ischemia, Alzheimer's disease, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). The latter belongs to a class of conformational diseases, known as serpinopathies, which are related to the aberrant polymerization of serpin mutants. Neuroserpin is known to polymerize, even in its wild type form, under thermal stress. Here, we study the mechanism of neuroserpin polymerization over a wide range of temperatures by different techniques. Our experiments show how the onset of polymerization is dependent on the formation of an intermediate monomeric conformer, which then associates with a native monomer to yield a dimeric species. After the formation of small polymers, the aggregation proceeds via monomer addition as well as polymer-polymer association. No further secondary mechanism takes place up to very high temperatures, thus resulting in the formation of neuroserpin linear polymeric chains. Most interesting, the overall aggregation is tuned by the co-occurrence of monomer inactivation (i.e. the formation of latent neuroserpin) and by a mechanism of fragmentation. The polymerization kinetics exhibit a unique modulation of the average mass and size of polymers, which might suggest synchronization among the different processes involved. Thus, fragmentation would control and temper the aggregation process, instead of enhancing it, as typically observed (e.g.) for amyloid fibrillation.