%0 Journal Article
%A Schulte, Marianne
%A Panwalkar, Vineet
%A Freischem, Stefan
%A Willbold, Dieter
%A Dingley, Andrew J.
%T Proline Restricts Loop I Conformation of the High Affinity WW Domain from Human Nedd4-1 to a Ligand Binding-Competent Type I β-Turn
%J The journal of physical chemistry  / B
%V 122
%N 15
%@ 1520-5207
%C Washington, DC
%I Soc.
%M FZJ-2018-02548
%P 4219 - 4230
%D 2018
%X Sequence alignment of the four WW domains from human Nedd4-1 (neuronal precursor cell expressed developmentally down-regulated gene 4-1) reveals that the highest sequence diversity exists in loop I. Three residues in this type I β-turn interact with the PPxY motif of the human epithelial Na+ channel (hENaC) subunits, indicating that peptide affinity is defined by the loop I sequence. The third WW domain (WW3*) has the highest ligand affinity and unlike the other three hNedd4-1 WW domains or other WW domains studied contains the highly statistically preferred proline at the (i + 1) position found in β-turns. In this report, molecular dynamics simulations and experimental data were combined to characterize loop I stability and dynamics. Exchange of the proline to the equivalent residue in WW4 (Thr) results in the presence of a predominantly open seven residue Ω loop rather than the type I β-turn conformation for the wild-type apo-WW3*. In the presence of the ligand, the structure of the mutated loop I is locked into a type I β-turn. Thus, proline in loop I ensures a stable peptide binding-competent β-turn conformation, indicating that amino acid sequence modulates local flexibility to tune binding preferences and stability of dynamic interaction motifs.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29595969
%U <Go to ISI:>//WOS:000430784000004
%R 10.1021/acs.jpcb.7b11637
%U https://juser.fz-juelich.de/record/845267