AQP2: Mutations Associated with Congenital Nephrogenic Diabetes Insipidus and Regulation by Post-Translational Modifications and Protein-Protein Interactions

Abstract

As a rare hereditary disease, congenital nephrogenic diabetes insipidus (NDI) is clinically characterized by polyuria with hyposthenuria and polydipsia. NDI results from collecting duct principal cell hyporesponsiveness or insensitivity to the antidiuretic action of arginine vasopressin (AVP). The principal cell-specific water channel aquaporin-2 (AQP2) plays an essential role in water reabsorption along osmotic gradients. The capacity to accumulate AQP2 in the apical plasma membrane in response to decreased fluid volume or increased plasma osmolality is critically regulated by the antidiuretic hormone AVP and its receptor 2 (AVPR2). Mutations in AVPR2 result in X-linked recessive NDI, the most common form of inherited NDI. Genetic defects in AQP2 cause autosomal recessive or dominant NDI. In this review, we provide an updated overview of the genetic and molecular mechanisms of congenital NDI, with a focus on the potential disease-causing mutations in AVPR2 and AQP2, the molecular defects in the AVPR2 and AQP2 mutants, post-translational modifications (i.e., phosphorylation, ubiquitination, and glycosylation) and various protein-protein interactions that regulate phosphorylation, ubiquitination, tetramerization, trafficking, stability, and degradation of AQP2.

UbiComb: A Hybrid Deep Learning Model for Predicting Plant-Specific Protein Ubiquitylation Sites

“…In the PTM process, a modification group is added to one or more amino acids to alter the physical and chemical properties of the proteins [ 4 ]. As stated in the literature, PTM sites are identified in the domains of proteins, which are associated with drug-target binding, and protein–protein interactions, which lead to drug discovery [ 5 , 6 ]. In the case of ubiquitylation PTM, the small regulatory protein ubiquitin, which is either as a single ubiquitin or a ubiquitin chain, binds with targeted lysine residues on the protein substrate, resulting in changes in the transcriptional and translational levels [ 7 , 8 ].…”

Novel AQP2 Mutations and Clinical Characteristics in Seven Chinese Families With Congenital Nephrogenic Diabetes Insipidus

“…The structure of AQP2 has been clarified at 4.9-Å resolution, except for the structure of intracellular domains (11). The trafficking and degradation of AQP2 are regulated by multiple post-translational modifications, including phosphorylation, ubiquitination and glycosylation (12,13). For example, AVP increases phosphorylation of AQP2 at ser256 and ser269, which is important for the accumulation of AQP2 (14)(15)(16).…”

Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus

“…AVP-V2R complex catalyzes the release of αs-GTP from the receptor-coupled stimulatory G protein (Gs), and activates adenylate cyclase (AC), followed by the increasement of the cyclic adenosine monophosphate (cAMP) concentration and activation of protein Kinase A (PKA). Then the translocation of aquaporin 2 (AQP2) was initiated from the intracellular storage vesicles pool to the apical plasma membrane for maintaining kidney water homeostasis 5 – 7 . Besides its classical biological effects, V2R can also initiate a mitogen-activated protein kinase (MAPK) cascade independent of the G protein, phosphorylating extracellular-regulated protein kinase (ERK1/2) and thus promoting the translocation of AQP2 8 – 10 .…”

“…Up to now, at least 287 AVPR2 gene mutations have been reported, including missense/nonsense mutations, small/ large fragment deletion, splicing site mutations and etc . , 177 of them are missense mutations, accounting for nearly 62% 5 , 14 . A few of gain-of-function mutations, such as R137C, R137L I130N and F229V that cause constitutive activation of receptors, leading to X-linked nephrogenic syndrome of inappropriate antidiuresis (NSIAD) 15 , 16 , while most of AVPR2 gene mutations are loss-of-function that cause X-linked nephrogenic diabetes insipidus (X-linked NDI) 7 , 17 , 18 .…”