Selectivity in the Post-Translational, Transglutaminase-Dependent Acylation of Lysine Residues

Murthy, S. N. Prasanna; Lukas, Thomas J.; Jardetzky, Theodore S.; Lóránd, L.

doi:10.1021/bi802323z

Cited by 15 publications

(17 citation statements)

References 51 publications

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“…But the Lys35 in SLPI lies within a WQCPGK sequence that resembles the proposed GQDPVK consensus transglutaminase substrate sequence of the cementoin domain of trappin-2. We were also unable to establish any correlation between the reactivity of the Gln and Lys residues and their accessibilty in the 3D structure of SLPI and the elafin moiety of trappin-2 (data not shown), in agreement with previous findings suggesting that other structural determinants in the vicinity of reactive residues are important [20], [21].…”

Section: Discussionsupporting

confidence: 87%

“…Furthermore, those lysines in the cementoin domain that are in the same sequence context as Lys44 (i.e included in a PVKG sequence) do not seem to react with TGase. This implies that TGase is remarkably specific for certain Gln and Lys sites in both trappin-2/elafin and SLPI, as it is for many other proteins [12], [20], [21]. Our results provide no clear consensus sequence around reactive Gln or Lys residues.…”

Section: Discussionmentioning

confidence: 61%

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Secretory Leukocyte Protease Inhibitor (SLPI) Is, like Its Homologue Trappin-2 (Pre-Elafin), a Transglutaminase Substrate

Baranger

Zani

Labas³

et al. 2011

PLoS ONE

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Human lungs contain secretory leukocyte protease inhibitor (SLPI), elafin and its biologically active precursor trappin-2 (pre-elafin). These important low-molecular weight inhibitors are involved in controlling the potentially deleterious proteolytic activities of neutrophil serine proteases including elastase, proteinase 3 and cathepsin G. We have shown previously that trappin-2, and to a lesser extent, elafin can be linked covalently to various extracellular matrix proteins by tissue transglutaminases and remain potent protease inhibitors. SLPI is composed of two distinct domains, each of which is about 40% identical to elafin, but it lacks consensus transglutaminase sequence(s), unlike trappin-2 and elafin. We investigated the actions of type 2 tissue transglutaminase and plasma transglutaminase activated factor XIII on SLPI. It was readily covalently bound to fibronectin or elastin by both transglutaminases but did not compete with trappin-2 cross-linking. Cross-linked SLPI still inhibited its target proteases, elastase and cathepsin G. We have also identified the transglutamination sites within SLPI, elafin and trappin-2 by mass spectrometry analysis of tryptic digests of inhibitors cross-linked to mono-dansyl cadaverin or to a fibronectin-derived glutamine-rich peptide. Most of the reactive lysine and glutamine residues in SLPI are located in its first N-terminal elafin-like domain, while in trappin-2, they are located in both the N-terminal cementoin domain and the elafin moiety. We have also demonstrated that the transglutamination substrate status of the cementoin domain of trappin-2 can be transferred from one protein to another, suggesting that it may provide transglutaminase-dependent attachment properties for engineered proteins. We have thus added to the corpus of knowledge on the biology of these potential therapeutic inhibitors of airway proteases.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 61%

Secretory Leukocyte Protease Inhibitor (SLPI) Is, like Its Homologue Trappin-2 (Pre-Elafin), a Transglutaminase Substrate

Baranger

Zani

Labas³

et al. 2011

PLoS ONE

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“…Transglutaminase enzymes (TGs) are transferases that catalyse the calcium dependant formation of inter- or intramolecular isopeptide bonds between proteins by crosslinking protein bound glutamine and lysine amino acids 37 . TGs are homologous to the papain family of proteases with which they share significant active site sequence and structural similarities 38 . During transglutamination, a glutamine side chain on a substrate protein is attacked by the active site Cys of a transglutaminase enzyme with formation of a thioester intermediate.…”

Section: Transglutaminationmentioning

confidence: 99%

“…TGs exhibit remarkable specificities not only for the Gln site of hydrolysis, but also for the Lys residue of proteins with which they react. Recent studies suggest that the specificity of Lys residues TGs is not encoded in the primary amino acid sequence surrounding the target Lys but is primarily dependant on its positioning in an accessible segment of the protein structure 38 .…”

Section: Transglutaminationmentioning

confidence: 99%

Exploring chemoselective S-to-N acyl transfer reactions in synthesis and chemical biology

2017

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S-to-N acyl transfer is a high-yielding chemoselective process for amide bond formation. It is widely utilized by chemists for synthetic applications, including peptide and protein synthesis, chemical modification of proteins, protein-protein ligation and the development of probes and molecular machines. Recent advances in our understanding of S-to-N acyl transfer processes in biology and innovations in methodology for thioester formation and desulfurization, together with an extension of the size of cyclic transition states, have expanded the boundaries of this process well beyond peptide ligation. As the field develops, this chemistry will play a central role in our molecular understanding of Biology.

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“…It is interesting to note that the overall kinetics of proteins release was observed to have the order: CytC<RNaseA<Lys (see SI). The release kinetics seems to correlate with the number of surface exposed lysines in each protein (CytC: 19, RNaseA: 10, Lys: 6 11 ). This is understandable, since the higher number of anchoring points requires more sites for the reducing agent to process during release.…”

mentioning

confidence: 99%

Templated Self-Assembly of a Covalent Polymer Network for Intracellular Protein Delivery and Traceless Release

et al. 2017

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Trafficking proteins inside cells is an emerging field with potential utility in basic cell biology and biological therapeutics. A robust and sustainable delivery strategy demands not only a good protection of the cargo, but also for reversibility in conjugation and activity. We report a protein-templated polymer self-assembly strategy for the formation of a sheath around the proteins and then tracelessly releasing them in the cytosol. The demonstrated versatility of the approach suggests that the strategy could be compatible with a wide array of biologics.

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Selectivity in the Post-Translational, Transglutaminase-Dependent Acylation of Lysine Residues

Cited by 15 publications

References 51 publications

Secretory Leukocyte Protease Inhibitor (SLPI) Is, like Its Homologue Trappin-2 (Pre-Elafin), a Transglutaminase Substrate

Secretory Leukocyte Protease Inhibitor (SLPI) Is, like Its Homologue Trappin-2 (Pre-Elafin), a Transglutaminase Substrate

Exploring chemoselective S-to-N acyl transfer reactions in synthesis and chemical biology

Templated Self-Assembly of a Covalent Polymer Network for Intracellular Protein Delivery and Traceless Release

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