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Characterisation of serpin polymers in vitro and in vivo
- Publication Year :
- 2011
- Publisher :
- ACADEMIC PRESS INC ELSEVIER SCIENCE, 2011.
-
Abstract
- Neuroserpin is a member of the serine protease inhibitor or serpin superfamily of proteins. It is secreted by neurones and plays an important role in the regulation of tissue plasminogen activator at the synapse. Point mutations in the neuroserpin gene cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. This is one of a group of disorders caused by mutations in the serpins that are collectively known as the serpinopathies. Others include α(1)-antitrypsin deficiency and deficiency of C1 inhibitor, antithrombin and α(1)-antichymotrypsin. The serpinopathies are characterised by delays in protein folding and the retention of ordered polymers of the mutant serpin within the cell of synthesis. The clinical phenotype results from either a toxic gain of function from the inclusions or a loss of function, as there is insufficient protease inhibitor to regulate important proteolytic cascades. We describe here the methods required to characterise the polymerisation of neuroserpin and draw parallels with the polymerisation of α(1)-antitrypsin. It is important to recognise that the conditions in which experiments are performed will have a major effect on the findings. For example, incubation of monomeric serpins with guanidine or urea will produce polymers that are not found in vivo. The characterisation of the pathological polymers requires heating of the folded protein or alternatively the assessment of ordered polymers from cell and animal models of disease or from the tissues of humans who carry the mutation.
- Subjects :
- Mutation, Missense
Epilepsies, Myoclonic
Serpin
Biology
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
Inclusion bodies
Mass Spectrometry
Protein Refolding
C1-inhibitor
Animals, Genetically Modified
Neuroserpin
medicine
Animals
Humans
Cloning, Molecular
Proteostasis Deficiencies
Familial encephalopathy with neuroserpin inclusion bodies
Molecular Biology
Serpins
Serine protease
Inclusion Bodies
Mutation
alpha-1 antitrypsin
conformational diseases
fenib
neuroserpin
serpin
Immune Sera
medicine.disease
Protease inhibitor (biology)
Disease Models, Animal
Drosophila melanogaster
Biochemistry
biology.protein
Heredodegenerative Disorders, Nervous System
Protein Multimerization
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....e32581922aa3e9fa5f040f80768289bd