Effects of diabetes insipidus mutations on neurophysin folding and function

Mechanisms underlying the pathogenicity of diabetes insipidus mutations wer e probed by studying their effects on the properties of bovine oxytocin-rel ated neurophysin. The mutations G17V, Delta E47, G57S, G57R, and C67STOP we re each shown to have structural consequences that would diminish the confo rmational stability and folding efficiency of the precursors in which they were incorporated, and factors contributing to the origins of these propert y changes were identified. Effects of the mutations on dimerization of the folded proteins were similarly analyzed. The projected relative impact of t he above mutations on precursor folding properties qualitatively parallels the reported relative severity of their effects on the biological handling of the human vasopressin precursor, but quantitative differences between th ermodynamic effects and biological impact are noted and explored. The sole mutation for which no clear thermodynamic basis was found for its pathogeni city was 87STOP, suggesting that the region of the precursor deleted by thi s mutation plays a role in targeting independent from effects on folding, o r participates in stabilizing interactions unique to the human vasopressin precursor.