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Functionally important interactions between the nucleotide-binding domains of an antigenic peptide transporter
1Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Biochemistry
|May 3, 2008
Summary
Electrostatic interactions between nucleotide-binding domains are crucial for transporter associated with antigen processing (TAP) function. These interactions regulate peptide transport, not ATP hydrolysis, supporting a closed transporter model.
Area of Science:
- Molecular Biology
- Immunology
- Biochemistry
Background:
- The transporter associated with antigen processing (TAP) is an ABC transporter essential for adaptive immunity.
- TAP facilitates peptide loading onto MHC class I molecules by transporting peptides from the cytosol into the endoplasmic reticulum.
- ATP binding and hydrolysis by TAP's nucleotide-binding domains (NBDs) energize this transport process.
Purpose of the Study:
- To investigate the role of electrostatic interactions between the two NBDs of TAP in peptide transport.
- To determine if these interactions are essential for ATP hydrolysis or other stages of the transport cycle.
Main Methods:
- Biochemical assays were used to study TAP function.
- Mutagenesis was employed to disrupt specific electrostatic interactions at the NBD interface.
Main Results:
- Two key electrostatic interactions were identified at the interface between the TAP NBDs.
- Disruption of these interactions via mutagenesis significantly impaired peptide transport.
- Mutating these interactions did not substantially affect ATP hydrolysis rates in isolated NBDs.
Conclusions:
- Electrostatic interactions between TAP NBDs are critical for peptide transport, likely by stabilizing a closed conformation during the transport cycle.
- These findings support a general model for ABC transporter function where NBDs undergo conformational changes.
- The study highlights the importance of conserved charged residues in homologous positions across different ABC transporters.
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