Polymorphisms and disease: hotspots of inactivation in methyltransferases

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tibs.2010.03.007 Byline: Karen Rutherford (1), Valerie Daggett (1)(2) Abstract: Methyltransferases catalyze the methylation processes essential for protein/DNA repair, transcriptional regulation, and drug metabolism in vivo. More than 500 human methyltransferase polymorphisms have been identified, many of which are linked to disease. We mapped all available coding polymorphisms of seven methyltransferases onto their structures to address their structural significance, and identified a polymorphic hotspot [approximately equal to]20A from the active site in four of the proteins. Molecular dynamics simulations of these proteins reveal a common mechanism of destabilization: the mutations alter important side-chain contacts within the polymorphic site that are propagated through the protein, thereby distorting the active site. We propose that this hotspot might have arisen to modulate enzymatic activity, with decreased activity actually conferring an advantage in three of the four methyltransferases. Author Affiliation: (1) Department of Biochemistry, Box 355013, University of Washington, Seattle WA 98195-5013, USA (2) Department of Bioengineering, Box 355013, University of Washington, Seattle WA 98195-5013, USA