MD simulations of the dsRBP DGCR8 reveal correlated motions that may aid pri-miRNA binding

Christopher Wostenberg, William George Noid, Scott A. Showalter

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Over the past decade, microRNAs (miRNAs) have been shown to affect gene regulation by basepairing with messenger RNA, and their misregulation has been directly linked with cancer. DGCR8, a protein that contains two dsRNAbinding domains (dsRBDs) in tandem, is vital for nuclear maturation of primary miRNAs (pri-miRNAs) in connection with the RNase III enzyme Drosha. The crystal structure of the DGCR8 Core (493-720) shows a unique, well-ordered structure of the linker region between the two dsRBDs that differs from the flexible linker connecting the two dsRBDs in the antiviral response protein, PKR. To better understand the interfacial interactions between the two dsRBDs, we ran extensive MD simulations of isolated dsRBDs (505-583 and 614-691 ) and the Core. The simulations reveal correlated reorientations of the two domains relative to one another, with the well-ordered linker and C-terminus serving as a pivot. The results demonstrate that motions at the domain interface dynamically impact the conformation of the RNA-binding surface and may provide an adaptive separation distance that is necessary to allow interactions with a variety of different pri-miRNAs with heterogeneous structures. These results thus provide an entry point for further in vitro studies of the potentially unique RNA-binding mode of DGCR8.

Original languageEnglish (US)
Pages (from-to)248-256
Number of pages9
JournalBiophysical journal
Volume99
Issue number1
DOIs
StatePublished - Jul 7 2010

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MicroRNAs
Ribonuclease III
Nucleic Acid Conformation
Antiviral Agents
Proteins
RNA
Messenger RNA
Enzymes
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biophysics

Cite this

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abstract = "Over the past decade, microRNAs (miRNAs) have been shown to affect gene regulation by basepairing with messenger RNA, and their misregulation has been directly linked with cancer. DGCR8, a protein that contains two dsRNAbinding domains (dsRBDs) in tandem, is vital for nuclear maturation of primary miRNAs (pri-miRNAs) in connection with the RNase III enzyme Drosha. The crystal structure of the DGCR8 Core (493-720) shows a unique, well-ordered structure of the linker region between the two dsRBDs that differs from the flexible linker connecting the two dsRBDs in the antiviral response protein, PKR. To better understand the interfacial interactions between the two dsRBDs, we ran extensive MD simulations of isolated dsRBDs (505-583 and 614-691 ) and the Core. The simulations reveal correlated reorientations of the two domains relative to one another, with the well-ordered linker and C-terminus serving as a pivot. The results demonstrate that motions at the domain interface dynamically impact the conformation of the RNA-binding surface and may provide an adaptive separation distance that is necessary to allow interactions with a variety of different pri-miRNAs with heterogeneous structures. These results thus provide an entry point for further in vitro studies of the potentially unique RNA-binding mode of DGCR8.",
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MD simulations of the dsRBP DGCR8 reveal correlated motions that may aid pri-miRNA binding. / Wostenberg, Christopher; Noid, William George; Showalter, Scott A.

In: Biophysical journal, Vol. 99, No. 1, 07.07.2010, p. 248-256.

Research output: Contribution to journalArticle

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