Membrane Protein Stability Analyses by Means of Protein Energy Profiles in Case of Nephrogenic Diabetes Insipidus

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.

eProS – A Bioinformatics Knowledgebase, Toolbox and Database for Characterizing Protein Function

“…For more information, please refer to the discussions in references [7,4,9]. The underlying coarse-grained energy model applied by eProS services utilizes concepts of statistical physics.…”

“…Recent studies have demonstrated that sequences of energy values, referred to as energy profiles, obtained from protein structures using fine and coarse-grained energy models can be used to characterize protein functionality and structural features [10,11,7,9]. Mrozek et al had introduced a dynamic programming approach for generating energy profile alignments [10,11].…”

“…To implement an automated energy profile generation pipeline for large-scale analyses thus becomes challenging. However, such analyses can be of interest in structural biology, as entire protein folds and families can be investigated in the focus of characterizing and understanding the energetic features that determine protein structure, stability and function [10,11,7,9].…”

“…As shown by Heinke et al [9,7,8] this model is capable to cope with the task of characterizing protein structure changes caused by protein-environment interactions. In these studies energy profiling was employed to investigate energetic changes in models of mutant aquaporin 2 structures -a key membrane protein in maintaining the body's water balance.…”

eProS—a database and toolbox for investigating protein sequence–structure–function relationships through energy profiles

“…The analyses of proteins based on energy profiles can contribute in understanding correspondences of protein sequence to structure, stability and function (7,10,11,21). However, the generation of large scale databases of energy profiles derived from physics-based approaches is difficult to automatize, error-prone and slow.…”