Trafficking of the Vasopressin and Oxytocin Prohormone Through the Regulated Secretory Pathway

Abstract

The trafficking of prohormones and of regulated secretory proteins in general has been studied extensively in the last decades of the last century. Prohormone trafficking starts with correct folding and subsequently efficient sorting into the secretory granule of the regulated secretory pathway. The vasopressin/oxytocin prohormone is particularly interesting for studying protein trafficking, because the physicochemical properties and three-dimensional structure have been largely elucidated. In the case of pro-vasopressin and pro-oxytocin, folding and sorting depend completely on both intramolecular and intermolecular interactions. Proper folding is guided by the hormone-neurophysin association and the sorting event relies on the aggregative properties of the neurophysin domain in the prohormone, as well as a specific sorting signal, which is revealed when the aggregative property of the neurophysin domain is deleted. A comprehensive mechanism for trafficking of the vasopressin/oxytocin prohormone from the endoplasmic reticulum to the secretory granule is proposed.

Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies

“…The exact nature of the these forms has not been precisely determined, but the proAVP protein signal peptide is known to have an unusual sequence, which makes the processing of the protein inefficient and allows for its missorting even under normal circumstances [49]. Moreover, proAVP oligomerization may be an integral part of its processing and trafficking [5][6][7], and higher molecular mass forms of proAVP have been found to be resistant to reduction by various agents [35,43,[45][46][47]. These forms and their stability may be a result of the 8 disulfide bridges within the 93 amino acids that comprise the VP-NP region of proAVP, and further structural complexity may be added as a result of oligomerization.…”

“…MAG1 also detected prominent bands at 38 kDa and at 20 kDa in human hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON) tissue extract, while NAB1 detected a single band at 38 kDa. The nature of these proAVP forms is not entirely known, however studies suggest that proAVP multimers exists as a product of VP-NP region-dependant interactions that may be resistant to reduction [5,6,35]. It does appear that some antibodies generated against proAVP are not able to readily react with all of the individual molecular mass forms that have been identified [35].…”

“…The biological functions of AVP are well denned, but those of VP-NP and VAG are not as well characterized. It is clear the VP-NP is important in the proper intracellular transport and processing of proAVP [5][6][7]. There are eight disulfide bridges within the 93 amino acids of the human VP-NP structure of proAVP, and further structural complexity is added through oligomerization.…”

“…There are eight disulfide bridges within the 93 amino acids of the human VP-NP structure of proAVP, and further structural complexity is added through oligomerization. The processing of proAVP is dependent not only on protein sequence, but also on this oligomerization [5][6][7]. Although VAG is conserved among most mammals, its precise function remains elusive.…”

NG peptides: A novel family of neurophysin-associated neuropeptides

“…Accordingly, mutations in the neurophysin domain of the human vasopressin gene can cause diabetes insipidus due to impaired vasopressin biosynthesis (Ivell and Richter, 1984;Legros and Geenen, 1996;De Bree and Burbach, 1998;De Bree, 2000). Genes encoding precursor proteins comprising a vasopressin/oxytocin-like peptide and a C-terminal neurophysin domain have been identified in vertebrates, deuterostomian invertebrates and protostomian invertebrates.…”