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Effect of methylation on the side-chain pKa value of arginine.

ABSTRACT: Arginine methylation is important in biological systems. Recent studies link the deregulation of protein arginine methyltransferases with certain cancers. To assess the impact of methylation on interaction with other biomolecules, the pKa values of methylated arginine variants were determined using NMR data. The pKa values of monomethylated, symmetrically dimethylated, and asymmetrically dimethylated arginine are similar to the unmodified arginine (14.2?±?0.4). Although the pKa value has not been significantly affected by methylation, consequences of methylation include changes in charge distribution and steric effects, suggesting alternative mechanisms for recognition.

SUBMITTER: Evich M

PROVIDER: S-EPMC4815340 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Effect of methylation on the side-chain pKa value of arginine.

Evich Marina M Stroeva Ekaterina E Zheng Yujun George YG Germann Markus W MW

Protein science : a publication of the Protein Society 20151125 2

Arginine methylation is important in biological systems. Recent studies link the deregulation of protein arginine methyltransferases with certain cancers. To assess the impact of methylation on interaction with other biomolecules, the pKa values of methylated arginine variants were determined using NMR data. The pKa values of monomethylated, symmetrically dimethylated, and asymmetrically dimethylated arginine are similar to the unmodified arginine (14.2 ± 0.4). Although the pKa value has not bee ...[more]

PMID: 26540340

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Project description:Coupled motions have been demonstrated to be functionally important in a number of enzymes. Noncovalent side-chain interactions play essential roles in coordinating the motions across different structural elements in a protein. However, most of the dynamic studies of proteins are focused on backbone amides or methyl groups in the side chains and little is known about the polar and charged side chains. We have previously characterized the conformational dynamics of deubiquitinase A (DUBA), an isopeptidase, on the microsecond-to-millisecond (μs-ms) time scales with the amide 1H Carr-Purcell-Meiboom-Gill (CPMG) experiment. We detected a global conformational exchange process on a time scale of approximately 200 μs, which involves most of the structural elements in DUBA, including the active site and the substrate binding interface. Here, we extend our previous study on backbone amides to the arginine side-chain Nε-Hε groups using a modified 1H CPMG pulse sequence that can efficiently detect both backbone amide and arginine side-chain Nε-Hε signals in a single experiment. We found that the side chains of three arginines display motions on the same time scale as the backbone amides. Mutations of two of the three arginines to alanines result in a decrease in enzyme activity. One of these two arginines is located in a loop involved in substrate binding. This loop is not visible in the backbone amide-detected experiments due to excess line broadening induced by motions on the μs-ms time scales. These results clearly demonstrate that the motions of some arginine side chains are coupled to the global conformational exchange process and provide an additional probe for motions in a functionally important loop that did not yield visible backbone amide signals, suggesting the value of side-chain experiments on DUBA. The modified 1H CPMG pulse sequence allows the simultaneous characterization of backbone and arginine side-chain dynamics without any increase in data acquisition time and can be applied to the dynamic studies of any protein that displays measurable amide 1H relaxation dispersion.

Dataset Information

Effect of methylation on the side-chain pKa value of arginine.

Publications

Effect of methylation on the side-chain pKa value of arginine.

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