Abstract
Diabetes insipidus (DI) is a rare endocrine, inheritable disorder with low incidences in an estimated one per 25,000–30,000 live births. This disease is characterized by polyuria and compensatory polydypsia. The diverse underlying causes of DI can be central defects, in which no functional arginine vasopressin (AVP) is released from the pituitary or can be a result of defects in the kidney (nephrogenic DI, NDI). NDI is a disorder in which patients are unable to concentrate their urine despite the presence of AVP. This antidiuretic hormone regulates the process of water reabsorption from the prourine that is formed in the kidney. It binds to its type-2 receptor (V2R) in the kidney induces a cAMP-driven cascade, which leads to the insertion of aquaporin-2 water channels into the apical membrane. Mutations in the genes of V2R and aquaporin-2 often lead to NDI. We investigated a structure model of V2R in its bound and unbound state regarding protein stability using a novel protein energy profile approach. Furthermore, these techniques were applied to the wild-type and selected mutations of aquaporin-2. We show that our results correspond well to experimental water ux analysis, which confirms the applicability of our theoretical approach to equivalent problems.
Highlights
Membrane proteins play important roles in many biological processes
The MEPAL of the V2R in bound and unbound state to arginine vasopressin (AVP) revealed energetic divergences in the surroundings of the amino acids Ala84 (Figure 5(a)), Ile130 (Figure 5(b)), and Pro322 (Figure 5(c)). This indicates that these amino acids are involved in hormone binding
Their mutations are well described in literature and cause a loss in functionality and hormone affinity [52,53,54,55,56]. This observation emphasizes the quality of the modeled AVP-V2R complex and the coarsegrained energy model discussed in this work
Summary
Membrane proteins play important roles in many biological processes. The total number of known membrane protein structures has increased from 337 to 1515 structures within the last eight years, the high degree of redundancy and the average quality of these structures reduce the overall condition of structural data significantly [1]. To investigate membrane protein structure and misfolding, other approaches, such as smallmolecular-force spectroscopy, have been applied and developed [4]. Mutation-induced membrane protein structure misfoldings are causes of many human diseases, that is, diabetes insipidus, hereditary deafness, retinitis pigmentosa, cystic fibrosis, familial hypercholesterolaemia, and so on [4,5,6,7]
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