Seminar

Serpin polymerisation: neuroserpin and alpha 1 antitrypsin related diseases

Elena Miranda Banos, PhD

Serpins are an ample family of evolutionary conserved proteins that inhibit serin proteases, mainly in the extracellular space. The inhibitory mechanism involves extensive conformational change in the serpin molecule, which needs to be very flexible. This renders serpins prone to destabilisation of the tertiary structure as a consequence of point mutations. Several aminoacidic changes have been reported in different serpins in connexion with human disease, many affecting alpha 1 antitrypsin and neuroserpin. In most cases, the mutant proteins form homopolymers that cannot exit the endoplasmic reticulum as efficiently as the wild type proteins. This causes cell toxicity and eventually disease, with a phenotype that depends on the specific serpin affected and the rate of polymerisation of the mutant protein. The exact mechanism of polymerisation and the pathways of cell toxicity are still under active research.