Transglutaminase factor XIII uses proteinase‐like catalytic triad to crosslink macromolecules

Pedersen, Lars C.; Yee, Vivien C.; Bishop, Paul D.; Trong, I. Le; Teller, David C.; Stenkamp, Ronald E.

doi:10.1002/pro.5560030720

Cited by 140 publications

(123 citation statements)

References 27 publications

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“…The N-terminal (Ϸ28 kDa) region of TG2 is responsible for binding fibronectin (8) whereas the C-terminal segment of barrel 2 could interact with phospholipase in signal transduction (14). The core domain comprises the papain-like catalytic center (15) and the nucleotidebinding residues (16). Like the monomeric but unlike the heterotrimeric G proteins, TG2 was shown to bind 2Ј-(or 3Ј)-O-(Nmethylanthraniloyl)GTP (mantGTP) with high affinity (17).…”

mentioning

confidence: 99%

Conserved tryptophan in the core domain of transglutaminase is essential for catalytic activity

Murthy

Iismaa

Begg

et al. 2002

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

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T ransglutaminase 2 [here designated TG2 (EC2.3.2.13), but also identified as the GTP-binding protein, G h ] differs from its relatives in the family of Ca 2ϩ -dependent protein crosslinking enzymes mainly by its affinity for nucleotides (1-3) and for fibronectin (4-8). GTP-binding and hydrolysis enable TG2 to act as a G protein in signal transduction (G h ; ref. 9); GTP also serves as a potent allosteric inhibitor that suppresses the Ca 2ϩ -activated crosslinking activities of the enzyme. Independently of any of its catalytic functions and GTP-binding activity, TG2 binds fibronectin with very high affinity (7). Thus, when expressed on cell surfaces, TG2 plays an important role in organizing the extracellular matrix as an integrin-binding adhesion coreceptor (10, 11).Crystal structures are available for two related proteins: the A subunit of the coagulation factor XIII zymogen (fXIIIA; ref. 12) and the sea bream liver TG (13). Although neither of these is regulated by GTP (personal information from Kohki Ishikawa regarding the latter enzyme), sequence homologies between TG2 (rat) and these proteins suggest that TG2͞G h also would be organized into four domains: a ␤ sandwich (residues 1-138) followed by a large ␣͞␤ catalytic core (139-471) and two ␤ barrels [barrel 1 (472-584) and barrel 2 (585-686)]. The N-terminal (Ϸ28 kDa) region of TG2 is responsible for binding fibronectin (8) whereas the C-terminal segment of barrel 2 could interact with phospholipase in signal transduction (14). The core domain comprises the papain-like catalytic center (15) and the nucleotidebinding residues (16). Like the monomeric but unlike the heterotrimeric G proteins, TG2 was shown to bind 2Ј-(or 3Ј)-O-(Nmethylanthraniloyl)GTP (mantGTP) with high affinity (17). Binding was evidenced also by the appearance of an energy transfer band from one or more Trp residues of the protein to the mant fluorophore in this nucleotide. Because the core domain contains almost all of the tryptophans conserved throughout the TG family, we evaluated the nucleotide-binding properties and the transamidating activities of candidate tryptophan point mutants of TG2. Specifically, W180, 241, 278, 332, and 337 were targeted because they surround S171, a residue identified to be critical for GTPbinding. On a model of TG2 based on the fXIIIA zymogen crystal structure (16), all of the mutated residues are within 20Å (range 9.3-18.7Å) of both S171 and the active-site cysteine C277. We show that no single Trp residue alone accounts for the observed energy transfer from the protein to the nucleotide but some of the tryptophan mutants displayed greatly diminished mantGTPbinding affinities. Another important finding was that residue W241-that is highly conserved among the TGs but is lacking in the catalytically inactive family member of human red cell, band 4.2-is critical for transamidation by TG2. Materials and MethodsConstructs. Site-directed mutants of rat TG2͞G h cDNA were generated in a temperature-cycling reaction with Pfu DNA polymerase by using two complement...

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confidence: 99%

Conserved tryptophan in the core domain of transglutaminase is essential for catalytic activity

Murthy

Iismaa

Begg

et al. 2002

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

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“…They are calcium-dependent enzymes that contain an active site consisting of a catalytic triad (Cys, His, Asp) (3)(4)(5). The six different classes of transglutaminases are participating in a wide variety of physiological processes (3,6,7).…”

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confidence: 99%

Consequences of Seven Novel Mutations on the Expression and Structure of Keratinocyte Transglutaminase

Huber¹,

Yee²,

Burri³

et al. 1997

Journal of Biological Chemistry

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“…Cerulenin was then manually positioned into this active site model of FXIII-A. Two constraints were placed on the positioning of the epoxide moiety; firstly the epoxide oxygen was placed in close proximity to the backbone N-H of C314 as a primary 'oxyanion hole' residue [3]. Secondly, the carbon atom immediately adjacent to the primary amide unit within cerulenin was placed within close proximity to the thiol moiety of C314, thus allowing the attack/ring opening of the epoxide moiety to occur.…”

Section: Resultsmentioning

confidence: 99%

“…Cellular FXIII however is composed only of the two A chains, suggesting the B domains are necessary for transportation of the catalytic A regions in blood plasma. Several crystal structures of human zymogen FXIII have been solved and consistently reveal the presence of a C314, H373, D396 triad [3]. Zymogen FXIII has no transglutaminase activity as the catalytic triad is buried deep in the core domain of the enzyme surrounded by two barrel domains, which block the entrance to the active site of the enzyme [4].…”

Section: Introductionmentioning

confidence: 99%

(±) cis-bisamido epoxides: A novel series of potent FXIII-A inhibitors

Avery

Pease

Smith

et al. 2015

European Journal of Medicinal Chemistry

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A novel class of potent FXIII-A inhibitors containing a (±) cis-bisamido epoxide pharmacophore is described. The compounds display highly potent inhibition of FXIII-A (IC 50 = 5-500 nM) in an in vitro assay. In contrast to other types of previously described covalent transglutaminase inhibitors, the bis-amido epoxides exhibited no measurable reactivity with glutathione, therefore possibly rendering this class of compounds suitable for future in vivo investigations. Additionally, the compounds show selective inhibition for FXIII-A against the cysteine protease, cathepsin S although they proved to have similar potency with a closely related transglutaminase, TGII, to that observed for FXIII-A.

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Transglutaminase factor XIII uses proteinase‐like catalytic triad to crosslink macromolecules

Cited by 140 publications

References 27 publications

Conserved tryptophan in the core domain of transglutaminase is essential for catalytic activity

Conserved tryptophan in the core domain of transglutaminase is essential for catalytic activity

Consequences of Seven Novel Mutations on the Expression and Structure of Keratinocyte Transglutaminase

(±) cis-bisamido epoxides: A novel series of potent FXIII-A inhibitors

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