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In silico study predicts a key role of RNA-binding domains 3 and 4 in nucleolin-miRNA interactions.
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  • Avdar San,
  • Dario Palmieri,
  • Anjana Saxena,
  • Shaneen Singh
Avdar San
Brooklyn College

Corresponding Author:asan@gradcenter.cuny.edu

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Dario Palmieri
The Ohio State University Wexner Medical Center
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Anjana Saxena
Brooklyn College
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Shaneen Singh
Brooklyn College
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Abstract

RNA binding proteins (RBPs) regulate many important cellular processes through their interactions with RNA molecules. RBPs are critical for post-transcriptional mechanisms keeping gene regulation in a fine equilibrium. Conversely, dysregulation of RBPs and RNA metabolism pathways is an established hallmark of tumorigenesis. Human nucleolin (NCL) is a multifunctional RBP that interacts with different types of RNA molecules, in part through its four RNA binding domains (RBDs). Particularly, NCL interacts directly with microRNAs (miRNAs) and is involved in their aberrant processing linked with many cancers, including breast cancer. Nonetheless, molecular details of the NCL-miRNA interaction remain obscure. In this study, we used an in silico approach to characterize how NCL targets miRNAs and whether this specificity is imposed by a definite RBD-interface. Here, we present structural models of NCL-RBDs and miRNAs, as well as predict scenarios of NCL- miRNA interactions generated using docking algorithms. Our study suggests a predominant role of NCL RBDs 3 and 4 (RBD3-4) in miRNA binding. We provide detailed analyses of specific motifs/residues at the NCL-substrate interface in both these RBDs and miRNAs. Finally, we propose that the evolutionary emergence of more than two RBDs in NCL in higher organisms coincides with its additional role/s in miRNA processing. Our study shows that RBD3-4 display sequence/structural determinants to specifically recognize miRNA precursor molecules. Moreover, the insights from this study can ultimately support the design of novel antineoplastic drugs aimed at regulating NCL-dependent biological pathways with a causal role in tumorigenesis.
25 Sep 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
28 Sep 2021Submission Checks Completed
28 Sep 2021Assigned to Editor
05 Oct 2021Reviewer(s) Assigned
29 Oct 2021Review(s) Completed, Editorial Evaluation Pending
09 Nov 2021Editorial Decision: Revise Major
17 Apr 20221st Revision Received
17 Apr 2022Submission Checks Completed
17 Apr 2022Assigned to Editor
17 Apr 2022Reviewer(s) Assigned
23 Apr 2022Review(s) Completed, Editorial Evaluation Pending
26 Apr 2022Editorial Decision: Accept
Nov 2022Published in Proteins: Structure, Function, and Bioinformatics volume 90 issue 11 on pages 1837-1850. 10.1002/prot.26355