Antagonistic role of Klotho-derived peptides dynamics in the pancreatic cancer treatment through obstructing WNT-1 and Frizzled binding

Biophysical Chemistry
Muhammad FakharSajid Rashid

Abstract

Klotho is an anti-aging protein that is engaged in the suppression of canonical WNT signaling. In this study, we investigated the expression pattern of human WNTs and Klotho in the pancreatic cancer. In the cancerous cells, WNT-1 exhibited much higher expression as compared to other WNTs, while no WNT expression was detected in the normal tissue. In contrast, Klotho expression was significantly low in the cancerous tissue. Based on these observations, we intended to explore Klotho binding to WNT-1 and cystein-rich domains (CRDs) of Frizzled (FZD) homologs through molecular docking and dynamics simulation assays. Interestingly, similar region of WNT-1 was detected in binding with Klotho and CRDs of FZD-1/2. FZD-CRDs were grasped by the association of peripheral hydrophobic residues of WNT-1 U-shaped cavity. Subsequently, WNT-1-bound Klotho-peptides were isolated and reevaluated for their binding abilities against WNT-1 and FZD-CRDs., The conformational readjustements of these complexes were deeply analyzed by calculating the size of WNT-1 U-shaped cavity. In comparison to apo-WNT-1, cavity opening was markedly enhanced (8.2 Å to 15.64 Å, 32.89 Å and 35.11 Å) in WNT-1-a, WNT-1-c and WNT-1-e complexes, respectively. Thus Klotho-de...Continue Reading

Citations

Sep 5, 2019·International Journal of Molecular Sciences·Monish Ram MakenaKartick C Pramanik
Jun 27, 2020·Cancers·Aishani SachdevaIrene Chong
Jul 1, 2020·The Journal of Clinical Investigation·Wakako KawarazakiToshiro Fujita
Feb 24, 2021·BMC Gastroenterology·Yang LiYamin Zhang
Feb 26, 2021·Nature Reviews. Nephrology·Wakako Kawarazaki, Toshiro Fujita
Apr 4, 2021·International Journal of Molecular Sciences·Wakako Kawarazaki, Toshiro Fujita

❮ Previous
Next ❯

Related Concepts

Related Feeds

ApoE Phenotypes

Apolipoprotein E (APOE) is a protein involved in fat metabolism and associated with the pathogenesis of Alzheimer's disease and cardiovascular disease. Here is the latest research on APOE phenotypes.