Dynamics, nanomechanics and signal transduction in reelin repeats

Karolina Mikulska-Ruminska,Janusz Strzelecki,Wieslaw Nowak

doi:10.1038/s41598-019-55461-8

Karolina Mikulska-Ruminska, Janusz Strzelecki + Show 1 more

Open Access

https://doi.org/10.1038/s41598-019-55461-8

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Abstract

Reelin is a large glycoprotein controlling brain development and cell adhesion. It regulates the positioning of neurons, as well as neurotransmission and memory formation. Perturbations in reelin signaling are linked to psychiatric disorders. Reelin participates in signal transduction by binding to the lipoprotein receptors VLDLR and ApoER2 through its central region. This part is rich in repeating BNR-EGF-BNR modules. We used standard molecular dynamics, steered molecular dynamics, and perturbation response scanning computational methods to characterize unique dynamical properties of reelin modules involved in signaling. Each module has specific sensors and effectors arranged in a similar topology. In the modules studied, disulfide bridges play a protective role, probably making both selective binding and protease activity of reelin possible. Results of single reelin molecule stretching by atomic force microscopy provide the first data on the mechanical stability of individual reelin domains. The forces required for partial unfolding of the modules studied are below 60 pN.

Highlights

Reelin is a large glycoprotein controlling brain development and cell adhesion
The analysis shows that effectors are buried inside bacterial neuraminidase repeats (BNR) domains whereas residues denoted as potential receivers of allosteric signals were identified in regions that are freely accessible to other molecules i.e. (i) the binding interface of apolipoprotein E receptor 2 (ApoER2) (Figs. 4, 5, underlined residues and yellow arrows), (ii) ion binding sites (Zn2+ or Ca2+) and (iii) a fragment of the epidermal growth factor (EGF) domain
We address the following questions: what is the effect of an external force applied to the central region of RELN? Which regions play a role of the buffer in RELN structure subject to tension? For this purpose, we used the steered Molecular dynamics (MD) (SMD) method to unfold each individual reelin BNR-EGF-BNR domains (BEB) structure localized in the central part of the protein

Summary

Introduction

Reelin is a large glycoprotein controlling brain development and cell adhesion. It regulates the positioning of neurons, as well as neurotransmission and memory formation. Reelin participates in signal transduction by binding to the lipoprotein receptors VLDLR and ApoER2 through its central region. This part is rich in repeating BNR-EGF-BNR modules. RELN, through relaying biological signals, is a major player in brain development and functioning[18] It has numerous functions outside neuronal tissues: there is a mounting evidence that reelin signaling mechanisms may promote migration of cancer cells[11]. RELN participates in canonical signaling by binding to the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2)[17] This event induces tyrosine phosphorylation of the adaptor protein disabled 1 (Dab1), a process mediated by Src kinases.

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