Dataset Information

Transamidase subunit GAA1/GPAA1 is a M28 family metallo-peptide-synthetase that catalyzes the peptide bond formation between the substrate protein's omega-site and the GPI lipid anchor's phosphoethanolamine.

ABSTRACT: The transamidase subunit GAA1/GPAA1 is predicted to be the enzyme that catalyzes the attachment of the glycosylphosphatidyl (GPI) lipid anchor to the carbonyl intermediate of the substrate protein at the ?-site. Its ~300-amino acid residue lumenal domain is a M28 family metallo-peptide-synthetase with an ?/? hydrolase fold, including a central 8-strand ?-sheet and a single metal (most likely zinc) ion coordinated by 3 conserved polar residues. Phosphoethanolamine is used as an adaptor to make the non-peptide GPI lipid anchor look chemically similar to the N terminus of a peptide.

SUBMITTER: Eisenhaber B

PROVIDER: S-EPMC4111754 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transamidase subunit GAA1/GPAA1 is a M28 family metallo-peptide-synthetase that catalyzes the peptide bond formation between the substrate protein's omega-site and the GPI lipid anchor's phosphoethanolamine.

Eisenhaber Birgit B Eisenhaber Stephan S Kwang Toh Yew TY Grüber Gerhard G Eisenhaber Frank F

Cell cycle (Georgetown, Tex.) 20140417 12

The transamidase subunit GAA1/GPAA1 is predicted to be the enzyme that catalyzes the attachment of the glycosylphosphatidyl (GPI) lipid anchor to the carbonyl intermediate of the substrate protein at the ω-site. Its ~300-amino acid residue lumenal domain is a M28 family metallo-peptide-synthetase with an α/β hydrolase fold, including a central 8-strand β-sheet and a single metal (most likely zinc) ion coordinated by 3 conserved polar residues. Phosphoethanolamine is used as an adaptor to make th ...[more]

PMID: 24743167

Similar Datasets

Project description:BackgroundThe transamidase complex is a molecular machine in the endoplasmic reticulum of eukaryotes that attaches a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins after cleaving a C-terminal propeptide with a defined sequence signal. Its five subunits are very hydrophobic; thus, solubility, heterologous expression and complex reconstruction are difficult. Therefore, theoretical approaches are currently the main source of insight into details of 3D structure and of the catalytic process.ResultsIn this work, we generated model 3D structures of the lumenal domain of human GPAA1, the M28-type metallo-peptide-synthetase subunit of the transamidase, including zinc ion and model substrate positions. In comparative molecular dynamics (MD) simulations of M28-type structures and our GPAA1 models, we estimated the metal ion binding energies with evolutionary conserved amino acid residues in the catalytic cleft. We find that canonical zinc binding sites 2 and 3 are strongest binders for Zn1 and, where a second zinc is available, sites 2 and 4 for Zn2. Zinc interaction of site 5 with Zn1 enhances upon substrate binding in structures with only one zinc. Whereas a previously studied glutaminyl cyclase structure, the best known homologue to GPAA1, binds only one zinc ion at the catalytic site, GPAA1 can sterically accommodate two. The M28-type metallopeptidases segregate into two independent branches with regard to one/two zinc ion binding modality in a phylogenetic tree where the GPAA1 family is closer to the joint origin of both groups. For GPAA1 models, MD studies revealed two large loops (flaps) surrounding the active site being involved in an anti-correlated, breathing-like dynamics.ConclusionsIn the light of combined sequence-analytic and phylogenetic arguments as well as 3D structural modelling results, GPAA1 is most likely a single zinc ion metallopeptidase. Two large flaps environ the catalytic site restricting access to large substrates.ReviewersThis article was reviewed by Thomas Dandekar (MD) and Michael Gromiha.

Dataset Information

Transamidase subunit GAA1/GPAA1 is a M28 family metallo-peptide-synthetase that catalyzes the peptide bond formation between the substrate protein's omega-site and the GPI lipid anchor's phosphoethanolamine.

Publications

Transamidase subunit GAA1/GPAA1 is a M28 family metallo-peptide-synthetase that catalyzes the peptide bond formation between the substrate protein's omega-site and the GPI lipid anchor's phosphoethanolamine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets