Exploring the allowed sequence space of a membrane protein.

We present a comprehensive view of the tolerance of a membrane protein to sequence substitution. We find that the protein, diacylglycerol kinase from Escherichia coli, is extremely tolerant to sequence changes with three-quarters of the residues tolerating non-conservative changes. The conserved residues are distributed with approximately the same frequency in the soluble and transmembrane portions of the protein, but the most critical active-site residues appear to residue in the second cytoplasmic domain. It is remarkable that a unique structure of the membrane embedded portion of the protein can be encoded by a sequence that is so tolerant to substitution.