Carbon-Oxygen Hydrogen Bonding in Biological Structure and Function

Horowitz, Scott; Trievel, Raymond C.

doi:10.1074/jbc.r112.418574

Cited by 275 publications

(265 citation statements)

References 74 publications

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“…The replacement of a hydrogen atom with a methyl group not only increases the steric bulk at that position in the peptide but also decreases the nucleophilicity of the linked nitrogen or sulfur atom. Methylation can also provide additional carbon-based hydrogen bond donors (25,26). These bonds can form when the carbon atom of the methyl group is bonded to a nitrogen atom bearing a net positive charge, as with the proline, histidine, and arginine methylated derivatives shown in the figure.…”

Section: Concluding Notesmentioning

confidence: 99%

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The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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Cellular physiology depends on the alteration of protein structures by covalent modification reactions. Using a combination of bioinformatic, genetic, biochemical, and mass spectrometric approaches, it has been possible to probe ribosomal proteins from the yeast Saccharomyces cerevisiae for posttranslationally methylated amino acid residues and for the enzymes that catalyze these modifications. These efforts have resulted in the identification and characterization of the first protein histidine methyltransferase, the first N-terminal protein methyltransferase, two unusual types of protein arginine methyltransferases, and a new type of cysteine methylation. Two of these enzymes may modify their substrates during ribosomal assembly because the final methylated histidine and arginine residues are buried deep within the ribosome with contacts only with RNA. Two of these modifications occur broadly in eukaryotes, including humans, while the others demonstrate a more limited phylogenetic range. Analysis of strains where the methyltransferase genes are deleted has given insight into the physiological roles of these modifications. These reactions described here add diversity to the modifications that generate the typical methylated lysine and arginine residues previously described in histones and other proteins. Regulation of biological function by protein methylation reactionsIt is more and more apparent just how much of biological function is dependent upon posttranslational modifications (1). The human genome encodes some 900 enzymes catalyzing just protein phosphorylation or ubiquitination (2,3). However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,4-8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10-12). Finally, we are discovering how alterations in protein methylation pathways can lead to human pathology, particularly in cancer (13-15).The collection of over sixty human protein arginine and lysine methyltransferases that leave histone "marks" recognized by reader proteins to guide gene expression are perhaps the poster children for the importance of protein methyltransferases (16-17). However, recent work has emphasized the importance of methylating non-histone substrates at these residues, particularly ribosomal proteins, translation factors, and transcription factors in a wide variety of organisms (7,8,15,18,19). Furthermore, the methylation of lysine and arginine residues represents just the tip of the iceberg in protein methylation -modifications have also been established at histidine, modified histidine (diphthamide), glutamate, glutamine, asparagine, Lisoaspartate, D-aspartate, cysteine, isoprenylcysteine, me...

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Section: Concluding Notesmentioning

confidence: 99%

“…An important recent discovery is that the three hydrogen atoms on methyl groups bound to positively charged nitrogen or sulfur atoms may themselves be able to serve as hydrogen bond donors, greatly expanding the possibilities for interactions (25,26; Figure 1). …”

Section: Regulation Of Biological Function By Protein Methylation Reamentioning

confidence: 99%

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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“….O type bond with carbon-5 or carbon-6 ( Fig. 2H; Horowitz and Trievel 2012). The interaction corresponding to the methyl-Arg contact is absent, but some stacking between the C ring and the side chain of Arg at position À7 continues (Fig.…”

Section: Structural Investigationsmentioning

confidence: 99%

Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence

et al. 2014

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In mammalian DNA, cytosine occurs in several chemical forms, including unmodified cytosine (C), 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5mC is a major epigenetic signal that acts to regulate gene expression. 5hmC, 5fC, and 5caC are oxidized derivatives that might also act as distinct epigenetic signals. We investigated the response of the zinc finger DNAbinding domains of transcription factors early growth response protein 1 (Egr1) and Wilms tumor protein 1 (WT1) to different forms of modified cytosine within their recognition sequence, 59-GCG(T/G)GGGCG-39. Both displayed high affinity for the sequence when C or 5mC was present and much reduced affinity when 5hmC or 5fC was present, indicating that they differentiate primarily oxidized C from unoxidized C, rather than methylated C from unmethylated C. 5caC affected the two proteins differently, abolishing binding by Egr1 but not by WT1. We ascribe this difference to electrostatic interactions in the binding sites. In Egr1, a negatively charged glutamate conflicts with the negatively charged carboxylate of 5caC, whereas the corresponding glutamine of WT1 interacts with this group favorably. Our analyses shows that zinc finger proteins (and their splice variants) can respond in modulated ways to alternative modifications within their binding sequence.

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“…Carbon hydrogen bonds are commonly observed in proteins and nucleic acids, where they can contribute to protein structure, recognition, or catalysis (6). Although carbons are generally weak donors, the Cα atom of all amino acids is activated by the electron withdrawing amide groups on both sides, and quantum calculations suggest that the energy of Cα-H hydrogen bonds may be as much as one-third to half of that of canonical donors in vacuum (7,8).…”

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confidence: 99%

A frequent, GxxxG-mediated, transmembrane association motif is optimized for the formation of interhelical Cα–H hydrogen bonds

Mueller

Subramaniam

Senes

2014

Proc. Natl. Acad. Sci. U.S.A.

143

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Carbon hydrogen bonds between Cα-H donors and carbonyl acceptors are frequently observed between transmembrane helices (Cα-H···O=C). Networks of these interactions occur often at helix−helix interfaces mediated by GxxxG and similar patterns. Cα-H hydrogen bonds have been hypothesized to be important in membrane protein folding and association, but evidence that they are major determinants of helix association is still lacking. Here we present a comprehensive geometric analysis of homodimeric helices that demonstrates the existence of a single region in conformational space with high propensity for Cα-H···O=C hydrogen bond formation. This region corresponds to the most frequent motif for parallel dimers, GAS right , whose best-known example is glycophorin A. The finding suggests a causal link between the high frequency of occurrence of GAS right and its propensity for carbon hydrogen bond formation. Investigation of the sequence dependency of the motif determined that Gly residues are required at specific positions where only Gly can act as a donor with its "side chain" Hα. Gly also reduces the steric barrier for nonGly amino acids at other positions to act as Cα donors, promoting the formation of cooperative hydrogen bonding networks. These findings offer a structural rationale for the occurrence of GxxxG patterns at the GAS right interface. The analysis identified the conformational space and the sequence requirement of Cα-H···O=C mediated motifs; we took advantage of these results to develop a structural prediction method. The resulting program, CATM, predicts ab initio the known high-resolution structures of homodimeric GAS right motifs at near-atomic level.interaction motifs | protein prediction

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Carbon-Oxygen Hydrogen Bonding in Biological Structure and Function

Cited by 275 publications

References 74 publications

The ribosome: A hot spot for the identification of new types of protein methyltransferases

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence

A frequent, GxxxG-mediated, transmembrane association motif is optimized for the formation of interhelical Cα–H hydrogen bonds

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