Exploring Molecular Contacts of MUC1 at CIN85 Binding Interface to Address Future Drug Design Efforts.

Maria Rita Gulotta,Ugo Perricone,Laura De Luca,Serena Vittorio,Rosaria Gitto

doi:10.3390/ijms22042208

Maria Rita Gulotta, Ugo Perricone + Show 3 more

Open Access

https://doi.org/10.3390/ijms22042208

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Abstract

The modulation of protein-protein interactions (PPIs) by small molecules represents a valuable strategy for pharmacological intervention in several human diseases. In this context, computer-aided drug discovery techniques offer useful resources to predict the network of interactions governing the recognition process between protein partners, thus furnishing relevant information for the design of novel PPI modulators. In this work, we focused our attention on the MUC1-CIN85 complex as a crucial PPI controlling cancer progression and metastasis. MUC1 is a transmembrane glycoprotein whose extracellular domain contains a variable number of tandem repeats (VNTRs) regions that are highly glycosylated in normal cells and under-glycosylated in cancer. The hypo-glycosylation fosters the exposure of the backbone to new interactions with other proteins, such as CIN85, that alter the intracellular signalling in tumour cells. Herein, different computational approaches were combined to investigate the molecular recognition pattern of MUC1-CIN85 PPI thus unveiling new structural information useful for the design of MUC1-CIN85 PPI inhibitors as potential anti-metastatic agents.

Highlights

This Cbl-b fragment consists of eleven amino acids, 902-PARPPKPRPRR-912, arranged in a polyproline II (PPII) helix conformation [15]
A computational workflow was carried out to investigate the molecular interactions between Mucin 1 (MUC1) and Cbl-interacting protein of 85 kDa (CIN85) SH3 domain providing useful information for the development of novel antitumoral drugs
The results showed that the most stable interactions in the trimeric complex of CIN85-MUC1 were in accordance with the X-ray solved structure CIN85-Cbl-b

Summary

Introduction

Protein-protein interactions (PPIs) have increasingly gained relevance within the scientific community as potential therapeutic targets due to their huge presence within the human organism and the involvement in several diseases. Human interactome includes about 130,000–650,000 PPI types implicated in different biological processes such as cell proliferation, apoptosis and signal transduction [1]. In-depth biological and clinical studies revealed that in cancers PPIs form hubs and nodes that affect intracellular signalling promoting tumorigenesis, tumour growth and metastasis formation. The modulation of PPIs by small molecules has been considered a challenging task, because of the large and flat interfaces of PPIs and, in this regard, they have been appointed as “undruggable” targets [3,4]. Research efforts led to the identification of new therapeutic agents targeting more than

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