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O-linked fucose and other post-translational modifications unique to EGF modules
1Department of Medicinal and Analytical Chemistry, Genentech, Inc., South San Francisco, CA 94080.
Glycobiology
|June 1, 1993
Summary
Three unusual post-translational modifications, including beta-hydroxyaspartate/asparagine and specific glycans, occur in epidermal growth factor homology (EGF) modules. These modifications, found in conserved sequences, may have unknown functions and relationships.
Area of Science:
- Biochemistry
- Molecular Biology
- Glycobiology
Background:
- Conserved amino acid sequences within epidermal growth factor homology (EGF) modules of multidomain proteins are sites for unusual post-translational modifications.
- These modifications include beta-hydroxyaspartate and beta-hydroxyasparagine, specific glycan structures like xylosylated glucose attached to serine, and fucosylation of threonine or serine residues.
Purpose of the Study:
- To identify and characterize novel post-translational modifications within EGF modules.
- To investigate the occurrence and consensus sequences of these modifications in various proteins.
- To explore the proximity and potential interplay of these modifications within protein structures.
Main Methods:
- Sequence analysis to identify conserved motifs associated with post-translational modifications.
- Identification of specific glycan structures and amino acid modifications through biochemical and mass spectrometry techniques.
- Comparative analysis across different proteins containing EGF modules.
Main Results:
- Discovery of beta-hydroxyaspartate and beta-hydroxyasparagine within specific cysteine-rich sequences in EGF modules.
- Characterization of (Xyl alpha 1-->3)Xyl alpha 1-->3Glc beta 1-->O-Ser glycans and Fuc alpha 1-->O-Thr/Ser modifications at conserved sites.
- Identification of a novel tetrasaccharide modification (NeuAc alpha 2-->6Gal beta 1-->4GlcNAc beta 1-->3Fuc alpha 1-->O-Ser) on human factor IX, extending O-fucosylation.
- Observation that multiple modifications can occur in close proximity, as seen in human factor IX.
- Finding that O-glycosidic modifications are typically restricted to N-terminal EGF modules, while beta-hydroxyaspartate/asparagine residues show no such restriction.
Conclusions:
- Multiple unusual post-translational modifications exist within EGF modules, suggesting complex regulatory mechanisms.
- The specific consensus sequences and locations of these modifications provide insights into protein structure and function.
- Further research is needed to elucidate the functional significance and interrelationships of these novel modifications.