A B−−Z junction induced by an A...A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

Kolimi, Narendar and Ajjugal, Yogeeshwar and Rathinavelan, Thenmalarchelvi (2017) A B−−Z junction induced by an A...A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein. Journal of Biological Chemistry. pp. 1-22. ISSN 0021-9258 (In Press)

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Abstract

GAC repeat expansion from five to seven in the exonic region of the gene for cartilage oligomeric matrix protein (COMP) leads to pseudoachondroplasia, a skeletal abnormality. However, the molecular mechanism by which GAC expansions in the COMP gene lead to skeletal dysplasias is poorly understood. Here, we used MD simulations which indicate that an A...A mismatch in a d(GAC)6.d(GAC)6 duplex induces negative supercoiling, leading to a local B−to−Z DNA transition. This transition facilitates the binding of d(GAC)7.d(GAC)7 with the Zα-binding domain of human adenosine deaminase acting on RNA 1 (ADAR1, hZαADAR1), as confirmed by CD, NMR and microscale thermophoresis studies. The CD results indicated that hZαADAR1 recognizes the zigzag backbone of d(GAC)7.d(GAC)7 at the B−Z junction and subsequently converts it into Z−DNA via the so-called passive mechanism. MD simulations carried out for the modeled hZαADAR1−d(GAC)6.d(GAC)6 complex confirmed the retention of previously reported important interactions between the two molecules. These findings suggest that hZαADAR1 binding with the GAC hairpin stem in COMP can lead to a non−genetic, RNA editing−mediated substitution in the COMP that may then play a crucial role in the development of pseudoachondroplasia.

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IITH Creators:

IITH Creators	ORCiD
Rathinavelan, Thenmalarchelvi	http://orcid.org/0000-0002-1142-0583

Item Type:

Article

Additional Information:

Indian Institute of Technology Hyderabad (IITH) (To TR). Ministry of Human Resources Development, Government of India provided fellowships to NK & YA.

Uncontrolled Keywords:

circular dichroism (CD); molecular dynamics; nuclear magnetic resonance (NMR); RNA editing; trinucleotide repeat disease; cartilage oligomeric matrix protein; human adar1 protein; pseudoachdroplasia

Subjects:

Others > Biotechnology

Divisions:

Department of Biotechnology

Depositing User:

Team Library

Date Deposited:

25 Sep 2017 05:04

Last Modified:

25 Sep 2017 05:04

URI:

http://raiithold.iith.ac.in/id/eprint/3577