Disordered Structural Ensembles of Vasopressin and Oxytocin and Their Mutants

Vasopressin and oxytocin are intrinsically disordered cyclic nonapeptides belonging to a family of neurohypophysial hormones. Although unique in their functions, these peptides differ only by two residues and both feature a tocin ring formed by the disulfide bridge between first and sixth cysteine residues. This sequence and structural similarity are experimentally linked to oxytocin agonism at vasopressin receptors and vasopressin antagonism at oxytocin receptors. Yet single- or double-residue mutations in both peptides have been shown to have drastic impacts on their activities at either receptor, and possibly the ability to bind to their neurophysin carrier protein. In this study we perform molecular dynamics simulations of the unbound native and mutant sequences of the oxytocin and vasopressin hormones to characterize their structural ensembles. We classify the subpopulations of these structural ensembles on the basis of the distributions of radius of gyration and secondary structure and hydrogen-bonding features of the canonical tocin ring and disordered tail region. We then relate the structural changes observed in the unbound form of the different hormone sequences to experimental information about peptide receptor binding, and more indirectly, carrier protein binding affinity, receptor activity, and protease degradation. This study supports the hypothesis that the structural characteristics of the unbound form of an IDP can be used to predict structural or functional preferences of its functional bound form

Hereditary Neurohypophyseal Diabetes Insipidus

Neurohypophyseal diabetes insipidus (DI) is most often caused by trauma, including operations, and infiltrating processes in the hypothalamic-pituitary region. Irradiation, ischemia, infections, or autoimmunity can also underlie the disease. Since the middle of the 19th century, familial forms of neurohypophyseal DI have been described. Most commonly, the disease is transmitted in an autosomal-dominant fashion; very rarely, autosomal-recessive inheritance has been observed. Hereditary neurohypophyseal DI is caused by mutations in the gene encoding the antidiuretic hormone vasopressin (AVP) and its carrier protein neurophysin II (NPII). Symptoms result from the lack of hormone, or from the inability of mutant AVP to activate its renal receptor, and respond to treatment with desmopressin (DDAVP). Dominant mutations cause retention of the hormone precursor in the endoplasmic reticulum (ER) of vasopressinergic neurons in the hypothalamus, resulting in cellular dysfunction and eventually neuronal death. This so-called "neurotoxicity hypothesis" was initially established on the basis of autopsy studies in affected humans and has been supported by heterologous cell-culture expression experiments and murine knock-in models. Current data show that retained mutants fail to be eliminated by the cell's quality control system and accumulate in fibrillar aggregations within the ER. Autosomal-dominant neurohypophyseal DI may thus be viewed as a neurodegenerative disease confined to vasopressinergic neurons

Familial forms of diabetes insipidus: clinical and molecular characteristics

Over the past two decades, the genetic and molecular basis of familial forms of diabetes insipidus has been elucidated. Diabetes insipidus is a clinical syndrome characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The most common type of diabetes insipidus is caused by lack of the antidiuretic hormone arginine vasopressin (vasopressin), which is produced in the hypothalamus and secreted by the neurohypophysis. This type of diabetes insipidus is referred to here as neurohypophyseal diabetes insipidus. The syndrome can also result from resistance to the antidiuretic effects of vasopressin on the kidney, either at the level of the vasopressin 2 receptor or the aquaporin 2 water channel (which mediates the re-absorption of water from urine), and is referred to as renal or nephrogenic diabetes insipidus. Differentiation between these two types of diabetes insipidus and primary polydipsia can be difficult owing to the existence of partial as well as complete forms of vasopressin deficiency or resistance. Seven different familial forms of diabetes insipidus are known to exist. The clinical presentation, genetic basis and cellular mechanisms responsible for them vary considerably. This information has led to improved methods of differential diagnosis and could provide the basis of new forms of therapy