Cytoprotective antioxidant function of tyrosine and tryptophan residues in transmembrane proteins.

The transmembrane domains of integral membrane proteins show an astounding accumulation of tyrosine and tryptophan residues, especially in the region of the highest lipid density. We found that these residues perform vital antioxidant functions inside lipid bilayers and protect cells from oxidative destruction. First, tyrosine- and tryptophan-containing peptides representing stretches from the transmembrane domains of different integral membrane proteins, including presenilin and the cystic fibrosis transmembrane conductance regulator, prevent oxidative lysis in clonal and primary cells. Second, long-chain acylated tyrosine and tryptophan, but not phenylalanine or short-chain acylated derivatives, are potent inhibitors of lipid peroxidation and oxidative cell death. The antioxidant functions of tyrosine and tryptophan may provide a specific explanation for (a) their unique transmembrane distribution pattern and (b) the high vulnerability of low-protein neuronal membranes to oxidative stress, as seen in neurodegenerative disorders.