Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=27766889
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins
using combination of protein engineering, protein-protein docking, peptide
docking and molecular dynamics simulations
#MMPMID27766889
Mirza SB
; Ekhteiari Salmas R
; Fatmi MQ
; Durdagi S
J Enzyme Inhib Med Chem
2017[Dec]; 32
(1
): 84-98
PMID27766889
show ga
The Klotho is known as lifespan enhancing protein involved in antagonizing the
effect of Wnt proteins. Wnt proteins are stem cell regulators, and uninterrupted
exposure of Wnt proteins to the cell can cause stem and progenitor cell
senescence, which may lead to aging. Keeping in mind the importance of Klotho in
Wnt signaling, in silico approaches have been applied to study the important
interactions between Klotho and Wnt3 and Wnt3a (wingless-type mouse mammary tumor
virus (MMTV) integration site family members 3 and 3a). The main aim of the study
is to identify important residues of the Klotho that help in designing peptides
which can act as Wnt antagonists. For this aim, a protein engineering study is
performed for Klotho, Wnt3 and Wnt3a. During the theoretical analysis of homology
models, unexpected role of number of disulfide bonds and secondary structure
elements has been witnessed in case of Wnt3 and Wnt3a proteins. Different in
silico experiments were carried out to observe the effect of correct number of
disulfide bonds on 3D protein models. For this aim, total of 10 molecular
dynamics (MD) simulations were carried out for each system. Based on the
protein-protein docking simulations of selected protein models of Klotho with
Wnt3 and Wnt3a, different peptides derived from Klotho have been designed. Wnt3
and Wnt3a proteins have three important domains: Index finger, N-terminal domain
and a patch of ?10 residues on the solvent exposed surface of palm domain.
Protein-peptide docking of designed peptides of Klotho against three important
domains of palmitoylated Wnt3 and Wnt3a yields encouraging results and leads
better understanding of the Wnt protein inhibition by proposed Klotho peptides.
Further in vitro studies can be carried out to verify effects of novel designed
peptides as Wnt antagonists.
free
free
free
