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Human genetics and disease

Serpinopathies and the conformational dementias

Abstract

The serpin superfamily of serine proteinase inhibitors has a central role in controlling proteinases in many biological pathways in a wide range of species. The inhibitory function of the serpins involves a marked conformational transition, but this inherent molecular flexibility also renders the serpins susceptible to point mutations that result in aberrant intermolecular linkage and polymer formation. The effects of such protein aggregation are cumulative, with a progressive loss of cellular function that results in diseases as diverse as cirrhosis and emphysema. The recent recognition that mutations in a serpin can also result in late-onset dementia provides insights into changes that underlie other conformational diseases, such as the amyloidoses, the prion encephalopathies and Huntington and Alzheimer diseases.

Key Points

  • The serpin superfamily of serine proteinase inhibitors has a central role in controlling proteinases in many biological pathways in a wide range of species. Serpins mediate their effects by a marked conformational transition that inactivates the target proteinase by translocating it from one end of the serpin to the other. This conformational transition is central to the role of serpins as effective antiproteinases but also renders them liable to undergo conformational change that leads to disease (the serpinopathies).

  • The serpinopathies are best characterized by α1-antitrypsin deficiency in humans, which arises from the retention of this serpin in hepatocytes and is associated with liver disease. Biochemical, biophysical, cell-biological and crystallographic studies have shown that α1-antitrypsin deficiency results from the sequential insertion of the reactive-centre loop of one α1-antitrypsin molecule in the β-sheet of another to form chains of polymers. This type of polymerization underlies the deficiency of other mutants of the serpins. For example, antithrombin, C1 inhibitor and α1-antichymotrypsin are associated with thrombosis, angio-oedema and emphysema, respectively.

  • Mutants of the neuron-specific serpin neuroserpin also polymerize by the same mechanism to cause the inclusion body dementia FENIB.

  • There is a striking correlation between the perturbation caused by a mutation, the rate of serpin polymerization and the severity of the clinical phenotype.

  • The polymerization that underlies the serpinopathies — caused by the insertion of the reactive loop into a β-sheet — provides a model for other conformational diseases that result from aberrant β-linkages.

  • The serpinopathies have similarities with the amyloidoses, the prion encephalopathies and Huntington and Alzheimer disease.

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Acknowledgements

This work is supported by the Medical Research Council (UK) and the Wellcome Trust. We are grateful to L. Serpell (University of Cambridge) for her helpful comments and for providing figure 4a, and to A. Lesk (University of Cambridge) for providing figure 4b.

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Correspondence to David A. Lomas.

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Glossary

β-LINKAGE

Intermolecular bonding between β-strands. In some cases, this might result from aligned β-strands, but in others, it arises from domain swaps; that is, the incorporation of a β-strand from one molecule into a β-sheet of another.

β-SHEETS

A polypeptide chain can fold back and forth on itself, with the strands being held together by interlinking hydrogen bonds with the peptide groups of neighbouring strands. This provides a very rigid structure that forms the core of many (but not all) proteins.

COMPLEMENT CASCADE

A proteolytic cascade that protects the host against infection. The components of the complement pathway coat and kill invading organisms and release inflammatory mediators. Its activation is controlled by the serpin C1 inhibitor.

FIBRINOLYTIC CASCADE

The breakdown (or lysis) of fibrin, which is the final product of the clotting cascade.

PSEUDOSUBSTRATE

A peptide sequence that is recognized by the enzyme as a substrate, but which then inactivates the proteinase.

ISOELECTRIC FOCUSING GELS

Thin-layer acrylamide gels that separate proteins by mass and charge. The different mutants of α1-antitrypsin have characteristic migration profiles.

PERIODIC ACID SCHIFF REACTION

(PAS). Periodic acid oxidizes some polysaccharides to produce aldehydes that react with the Schiff reagent. Inclusions of mutants of α1-antitrypsin in hepatocytes and mutants of neuroserpin in neurons stain positive for PAS but are resistant to treatment with salivary amylase (diastase).

CIRRHOSIS

Diffuse damage and fibrosis of the liver that is associated with nodules of regenerating hepatocytes. The common causes include chronic infection with hepatitis viruses B and C and prolonged alcohol abuse. It might also result from the accumulation of the Z variant of α1-antitrypsin.

SHUTTER DOMAIN

The region of a serpin that controls opening of the A-sheet and acceptance of the reactive centre loop. Mutations in this domain allow the acceptance of the reactive loop of another molecule and hence the formation of polymers.

ANGIO-OEDEMA

A clinical syndrome that results from a true or functional deficiency of the plasma protein C1 inhibitor. The deficiency results in unchecked activation of the complement cascade and the production of vasoactive mediators. It might have an autosomal-dominant pattern of inheritance and is characterized by swelling of the skin, bowel and larynx.

EMPHYSEMA

Abnormal enlargement of the airspaces (alveoli) after they divide from the terminal bronchi (airways). The most common cause is smoking but genetic deficiency of α1-antitrypsin predisposes some individuals to emphysema at an early age.

EOSINOPHILIC

Containing the white blood cells eosinophils. The cytoplasm of eosinophils is filled with coarse, refractile granules that stain intensely with acid dyes.

SUBSTANTIA NIGRA

A pigmented band of grey matter in the midbrain. Neuronal degeneration of this tract results in Parkinson disease, which is characterized by a slow tremor, rigidity and difficulty in initiating movements.

BIREFRINGENCE

The splitting of an incident wave into two waves of different velocities and orthogonal polarizations.

DOPAMINE

A chemical neurotransmitter that is found in high concentrations in the substantia nigra.

CHAPERONES

A protein that aids the folding of another to prevent it from taking an inactive conformation.

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Figure 1: Conformational transition of serpin family members.
Figure 2: Z α1-antitrypsin is retained in hepatocytes as intracellular inclusions.
Figure 3: Mutations of the serpins in the shutter domain.
Figure 4: Proposed models for the amyloidoses.
Figure 5: The design of a selective inhibitor to block the polymerization of Z α1-antitrypsin.