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

Biophysical Journal
Christopher WostenbergScott A Showalter

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 dsRNA-binding 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 ...Continue Reading

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Citations

May 21, 2013·Progress in Biophysics and Molecular Biology·Yury E Shapiro
Dec 29, 2012·PloS One·Christopher WostenbergScott A Showalter
Oct 15, 2013·Wiley Interdisciplinary Reviews. RNA·Allen W Nicholson
Mar 18, 2016·Journal of Chemical Theory and Computation·Casey Anne ColeHomayoun Valafar
Jun 23, 2016·Biophysical Journal·Roderico AcevedoScott A Showalter
Jan 22, 2015·PloS One·Roderico AcevedoScott A Showalter
Jun 21, 2012·The Journal of Physical Chemistry Letters·Dong Long, Rafael Brüschweiler

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