Issue 7, 2016

Elucidation, functional clustering and structural characterization of βTrCP1 substrates through a molecular dynamics study

Abstract

The current interest in the identification and characterization of βTrCP1 substrates necessitates a promising approach with broad structural constraints of WD40 potential binding sites. Here, we employed an in silico integrative approach to identify putative novel substrates of βTrCP1. Through a screened degradation motif (DSGXXS) for the entire human proteome and comparative substrate binding analysis of βTrCP1, we identified 344 substrates, sharing high sequence similarity with the consensus motif. Subsequent filtering on the basis of functional annotation and clustering resulted in the isolation of hits having clear roles in various cancer types. These substrates were phosphorylated at the Ser residues (Ser14 and Ser18) of the conserved motif. A comprehensive and thorough analysis of βTrCP1–phosphopeptide association indicated residual contributions located at the upper face of the β-propeller. Evidently, upon binding to phosphopeptides, the central channel of βTrCP1 attains a more open conformation to assist substrate binding. To elaborate the oncogenic function of βTrCP1, the SKP1–βTrCP1–CDH6 ternary complex was docked against CUL1–RBX1 and the acquired model exactly resembled the previously characterized SKP1–βTrCP1–β-catenin model. Overall, a deeper understanding of substrate targeting mechanisms coupled with the structural knowledge of βTrCP1 and associated proteins will be useful for designing novel targets for cancer therapeutics.

Graphical abstract: Elucidation, functional clustering and structural characterization of βTrCP1 substrates through a molecular dynamics study

Supplementary files

Article information

Article type
Paper
Submitted
10 mar 2016
Accepted
26 apr 2016
First published
26 apr 2016

Mol. BioSyst., 2016,12, 2233-2246

Elucidation, functional clustering and structural characterization of βTrCP1 substrates through a molecular dynamics study

S. Shafique, S. Younis, H. Niaz and S. Rashid, Mol. BioSyst., 2016, 12, 2233 DOI: 10.1039/C6MB00189K

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements