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. 2014 Jan;70(Pt 1):48-57.
doi: 10.1107/S139900471302364X. Epub 2013 Dec 24.

Lysine Carboxylation: Unveiling a Spontaneous Post-Translational Modification

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Free PMC article

Lysine Carboxylation: Unveiling a Spontaneous Post-Translational Modification

David Jimenez-Morales et al. Acta Crystallogr D Biol Crystallogr. .
Free PMC article

Abstract

The carboxylation of lysine residues is a post-translational modification (PTM) that plays a critical role in the catalytic mechanisms of several important enzymes. It occurs spontaneously under certain physicochemical conditions, but is difficult to detect experimentally. Its full impact is unknown. In this work, the signature microenvironment of lysine-carboxylation sites has been characterized. In addition, a computational method called Predictor of Lysine Carboxylation (PreLysCar) for the detection of lysine carboxylation in proteins with available three-dimensional structures has been developed. The likely prevalence of lysine carboxylation in the proteome was assessed through large-scale computations. The results suggest that about 1.3% of large proteins may contain a carboxylated lysine residue. This unexpected prevalence of lysine carboxylation implies an enrichment of reactions in which it may play functional roles. The results also suggest that by switching enzymes on and off under appropriate physicochemical conditions spontaneous PTMs may serve as an important and widely used efficient biological machinery for regulation.

Keywords: PreLysCar; Predictor of Lysine Carboxylation; lysine carboxylation; metal-ion centers; spontaneous post-translational modifications; structural motif.

Figures

Figure 1
Figure 1
Composition of the microenvironment of KCX sites and LYS sites (buried and surface lysine residues). Frequency of amino acids, metal ions and water molecules found within 5 Å of the side chain of Kcx (black bars), buried Lys (magenta bars) and surface Lys (gray bars) residues (see also Supplementary Tables S2 and S3). The amino acids found in the microenvironments are grouped according to their main physicochemical properties, i.e. positively charged (Arg, Lys and His), negatively charged (Asp and Glu), aromatic (Trp, Phe and Tyr) and hydrophobic (Ile, Leu, Val and Met) residues. The x axis represents the number of amino acids around the KCX and LYS sites, while the y axis represents the frequencies of each count.
Figure 2
Figure 2
Defining features of KCX sites. (a) Examples of proteins requiring functional carboxylated lysine residues. Examples of Kcx as a co-catalytic determinant involved in the formation of binuclear and mononuclear metal-ion centers (e.g. urease and RuBisCo, respectively) and Kcx as a catalytic determinant (e.g. class D β-lactamase). (b) Dispersion along protein sequences of amino acids that are part of the KCX site. Gray bars represent protein sequences, which are scaled for comparison. Cyan portions represent the fragment from the first to the last of the amino acids found in KCX sites. Yellow dots represent amino acids that are part of the KCX site and the red dot represents the Kcx residue (only 1ejx, 3kdn and 3isg shown). The left axis shows the PDB code (PDB ID) and the right axis the percentage of the extent of the protein sequences that the KCX sites occupy. A lack of a sequence motif was concluded (see Supplementary Fig. S1) (c) Summary of metal-ion center motifs. The side chains of the residues interacting with the metal ion are given in parentheses. For example, (H,H,D)Zn represents the side chains of two His residues and one Asp residue interacting with a zinc ion. Kcx side chains can either interact with one ion, e.g. (H,H,D)Zn· · ·KCX, or can bridge two metal ions, e.g. (H,H,D)Zn· · ·KCX· · ·Zn(H,H). The stick representation shows detail of the metal-ion centers of urease and RuBisCo.
Figure 3
Figure 3
Remodeling of Lys84, predicted to be carboxylated, to Kcx84 in carbapenemase OXA-24 (PDB entry 2jc7). (a) shows Lys84 highlighted in stick representation as reported in the structural coordinates (Santillana et al., 2007 ▶). The 2F oF c electron-density map around Lys84 is shown as a gray mesh and is contoured at 1σ. The F oF c map is shown in green and is contoured at 3σ. (b) shows the 2F oF c map around Lys84 after refinement with REFMAC (Murshudov et al., 2011 ▶) and with the Lys84 modified to include the PTM. This figure was created with PyMOL (Schrödinger; http://www.pymol.org).

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