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.

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)6d(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.

• Authors: Narendar Kolimi, Yogeeshwar Ajjugal, Thenmalarchelvi Rathinavelan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 46 Pg. 18732-18746 (11 17 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28924040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• COMP protein, human
• Cartilage Oligomeric Matrix Protein
• DNA, B-Form
• DNA, Z-Form
• RNA-Binding Proteins
• ADAR protein, human
• Adenosine Deaminase

Topics

• Achondroplasia (genetics, metabolism)
• Adenosine Deaminase (chemistry, metabolism)
• Base Pair Mismatch
• Cartilage Oligomeric Matrix Protein (chemistry, genetics)
• DNA, B-Form (chemistry, genetics, metabolism)
• DNA, Z-Form (chemistry, genetics, metabolism)
• Humans
• Molecular Dynamics Simulation
• Nucleic Acid Conformation
• Protein Binding
• Protein Domains
• RNA Editing
• RNA-Binding Proteins (chemistry, metabolism)
• Trinucleotide Repeats