NDLI: 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

Content Provider	Journal of Biological Chemistry (JBC)
Author	Kolimi, Narendar Ajjugal, Yogeeshwar Rathinavelan, Thenmalarchelvi
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 molecular dynamics 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. Molecular dynamics 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 COMP that may then play a crucial role in the development of pseudoachondroplasia.
Related Links	http://www.jbc.org/content/292/46/18732.abstract
Ending Page	18746
Starting Page	18732
Page Count	15
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	46
Volume Number	292
DOI	10.1074/jbc.M117.796235
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2017-11-17
Access Restriction	Open
Subject Keyword	CD Molecular dynamics NMR RNA editing Trinucleotide repeat disease Cartilage oligomeric matrix protein Human adar1 protein Pseudoachdroplasia Computational Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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