A structural determinant of human cytomegalovirus US2 dictates the down-regulation of class I major histocompatibility molecules
| Autor: | Vanessa M. Noriega, Laura P. Andrews, Kristina Oresic, Domenico Tortorella |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Viral protein
Mutant Molecular Sequence Data Cytomegalovirus Down-Regulation Genes MHC Class I CD8-Positive T-Lymphocytes Major histocompatibility complex medicine.disease_cause Biochemistry Protein Structure Secondary Serine Viral Envelope Proteins Cell Line Tumor MHC class I medicine Humans Amino Acid Sequence Molecular Biology Cell Proliferation biology Endoplasmic reticulum Histocompatibility Antigens Class I Cell Biology Cell biology Gene Expression Regulation Neoplastic Cytoplasm biology.protein Mutagenesis Site-Directed CD8 |
| Zdroj: | The Journal of biological chemistry. 281(28) |
| ISSN: | 0021-9258 |
| Popis: | Human cytomegalovirus down-regulates cell surface class I major histocompatibility (MHC) molecules, thus allowing the virus to proliferate while avoiding detection by CD8+ T lymphocytes. The unique short gene product US2 is a 199-amino acid type I endoplasmic reticulum glycoprotein that modulates surface expression of class I MHC products by targeting class I heavy chains for dislocation from the endoplasmic reticulum to the cytosol, where they undergo proteasomal degradation. Although the mechanism by which this viral protein targets class I heavy chains for destruction remains unclear, the putative US2 cytoplasmic tail comprised of only 14 residues is known to play a functional role. To determine the specific residues critical for mediating class I degradation, a mutagenesis analysis of the cytoplasmic tail of US2 was performed. Using truncation mutants, the removal of only 4 residues (mutant US2(195)) from the US2 carboxyl terminus completely abolishes class I destruction. Furthermore, site-directed mutagenesis of the US2 cytoplasmic tail revealed that the most critical residues for class I-induced destruction, cysteine 187, serine 190, tryptophan 193, and phenylalanine 196, occurs every third residue. This experimental data supports a model that the US2 cytoplasmic tail is in a 3(10) helical configuration. Such a secondary structure would predict that one side of the 3(10) helical cytoplasmic tail would interact with the extraction apparatus to facilitate the dislocation and subsequent destruction of class I heavy chains. |
| Databáze: | OpenAIRE |
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