γ‐Carboxyglutamic Acid (<scp>Gla</scp>) Domains

Stenberg, Leisa M.; Brown,; Stenflo, Johan

doi:10.1002/0471203076.emm0054

Wiley Encyclopedia of Molecular Medicine 2002

DOI: 10.1002/0471203076.emm0054

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γ‐Carboxyglutamic Acid (Gla) Domains

Leisa M. Stenberg

Brown Brown

Johan Stenflo

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2005

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“…Historically, the γ-carboxylase has been studied in the context of vertebrate hemostasis, as several proteins involved in blood coagulation or its regulation must be γ-carboxylated to be biologically active. Proteins with roles in bone mineralization, the extracellular matrix, and signal transduction are also substrates for the γ-carboxylase ( , ). Moreover, the γ-carboxylase plays an important role in the biology of at least one invertebrate.…”

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Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation^,

et al. 2005

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Vitamin K-dependent gamma-glutamyl carboxylase catalyzes the conversion of glutamyl residues to gamma-carboxyglutamate. Its substrates include vertebrate proteins involved in blood coagulation, bone mineralization, and signal transduction and invertebrate ion channel blockers known as conotoxins. Substrate recognition involves a recognition element, the gamma-carboxylation recognition site, typically located within a cleavable propeptide preceding the targeted glutamyl residues. We have purified two novel gamma-carboxyglutamate-containing conotoxins, Gla-TxX and Gla-TxXI, from the venom of Conus textile. Their cDNA-deduced precursors have a signal peptide but no apparent propeptide. Instead, they contain a C-terminal extension that directs gamma-carboxylation but is not found on the mature conotoxin. A synthetic 13-residue "postpeptide" from the Gla-TxXI precursor reduced the K(m) for the reaction of the Conus gamma-carboxylase with peptide substrates, including FLEEL and conantokin-G, by up to 440-fold, regardless of whether it was positioned at the N- or C-terminal end of the mature toxin. Comparison of the postpeptides to propeptides from other conotoxins suggested some common elements, and amino acid substitutions of these residues perturbed gamma-carboxylation of the Gla-TxXI peptide. The demonstration of a functional and transferable C-terminal postpeptide in these conotoxins indicates the presence of the gamma-carboxylation recognition site within the postpeptide and defines a novel precursor structure for vitamin K-dependent polypeptides. It also provides the first formal evidence to prove that gamma-carboxylation occurs as a post-translational rather than a cotranslational process.

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Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation^,

et al. 2005

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γ‐Carboxyglutamic Acid (Gla) Domains

Cited by 1 publication

References 18 publications

Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation^,

Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation^,

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γ‐Carboxyglutamic Acid (Gla) Domains

Cited by 1 publication

References 18 publications

Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation,

Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation,

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Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation^,

Precursors of Novel Gla-Containing Conotoxins Contain a Carboxy-Terminal Recognition Site That Directs γ-Carboxylation^,