Structural and Biophysical Insights into the Ligand-free Pitx2 Homeodomain and a Ring Dermoid of the Cornea Inducing Homeodomain Mutant

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2012 Jan 10

PMID 22224469

Citations 6

Authors

Thomas Doerdelmann

Douglas J Kojetin

Jamie M Baird-Titus

Laura A Solt

Thomas P Burris

Mark Rance

Affiliations

Soon will be listed here.

Abstract

The homeodomain-containing transcription factor Pitx2 (pituitary homeobox protein 2) is present in many developing embryonic tissues, including the heart. Its homeodomain is responsible for the recognition and binding to target DNA sequences and thus constitutes a major functional unit in the Pitx2 protein. Nuclear magnetic resonance techniques were employed to determine the solution structure of the native Pitx2 homeodomain and a R24H mutant that causes autosomal dominantly inherited ring dermoid of the cornea syndrome. The structures reveal that both isoforms possess the canonical homeodomain fold. However, the R24H mutation results in a 2-fold increase in DNA binding affinity and a 5 °C decrease in thermal stability, while changing the dynamic environment of the homeodomain only locally. When introduced into full-length Pitx2c, the mutation results in an only 25% loss of transactivation activity. Our data correlate well with clinical observations suggesting a milder deficiency for the R24H mutation compared to those of other Pitx2 homeodomain mutations.

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