Amyloid-like aggregation of provasopressin

Area of Science:

• Molecular Biology
• Cell Biology
• Neuroendocrinology

Background:

• The antidiuretic hormone vasopressin is synthesized as a precursor protein, provasopressin.
• Provasopressin undergoes folding, processing, and packaging through the secretory pathway, including the endoplasmic reticulum (ER) and trans-Golgi network (TGN).
• Mutations in provasopressin lead to autosomal dominant diabetes insipidus due to impaired folding and aggregation in the ER.

Purpose of the Study:

• To investigate the role of specific protein segments in both pathological and physiological aggregation of vasopressin.
• To determine the impact of ER quality control mechanisms on wild-type provasopressin aggregation.
• To explore the potential for similar aggregation mechanisms in other peptide hormones.

Main Methods:

• Analysis of provasopressin precursor protein folding and aggregation.
• Investigation of secretory granule formation in the TGN.
• Assessment of ER-associated degradation pathways, including Sel1L and Hrd1.
• Study of mutant and wild-type provasopressin aggregation in vasopressinergic neurons in mice.

Main Results:

• Specific segments of provasopressin are responsible for both pathological aggregation in the ER and physiological aggregation during secretory granule formation.
• Wild-type provasopressin can aggregate in the ER but is normally cleared by ER-associated degradation.
• Inactivation of ER quality control components (Sel1L, Hrd1) leads to fibrillar aggregation of wild-type provasopressin and diabetes insipidus in mice.

Conclusions:

• The evolution of amyloidogenic sequences for physiological granule formation makes provasopressin susceptible to ER aggregation.
• Provasopressin processing is critically dependent on cellular quality control mechanisms within the ER.
• These findings suggest that similar principles of protein aggregation and quality control may be relevant for other peptide hormones.