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.