Molecular mousetraps and the serpinopathies

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• The serpin superfamily of proteins regulates serine proteinases via a unique conformational change.
• Specific mutations in serpins cause misfolding and the formation of ordered polymers.
• These polymers accumulate within cells, leading to endoplasmic reticulum retention.

Discussion:

• Mutations in alpha(1)-antitrypsin and neuroserpin cause polymer retention in hepatocytes and neurons, leading to cirrhosis and dementia.
• Defective secretion of other serpins like antithrombin and C1 inhibitor results in plasma deficiency, causing thrombosis and angioedema.
• These diverse clinical conditions share a common molecular basis, now termed serpinopathies.

Key Insights:

• Serpinopathies arise from a shared mechanism of ordered polymer formation due to point mutations.
• Cellular retention and plasma deficiency are direct consequences of this polymerization.
• The conformational flexibility of serpins is crucial for their inhibitory function and susceptible to pathogenic mutations.

Outlook:

• Understanding the structural basis of serpin polymerization is key to developing specific therapeutic agents.
• Targeting the polymerization process offers a unified strategy for treating various serpinopathies.
• Future research may focus on stabilizing the native serpin conformation or enhancing clearance of toxic polymers.