One goal in our mission to understand the complexity of a biological system, is to be able to observe it “as it is,” i.e., to have access to the information contained in its components without altering the system itself. It is critical to consider this goal when studying transmembrane peptides given that incorporating labels may alter the structures or the environments. Early membrane models predicted that transmembrane proteins are stable due to the high proportion of hydrophobic amino acids within their sequence, but in nature, a significant fraction of residues in the interior of the membrane are polar. The challenge is not only to observe the native system, but also to understand the reason behind the presence of these hydrophilic residues. Our study strategizes towards these goals by taking a combined experimental and computational approach that uses the membrane peptide itself as an experimental probe.
The cover image for the May 7 issue of the Biophysical Journal is local Austin artist Heidi Lowell's representation of a transmembrane helix as a reporter of its own local environment. This watercolor painting includes a pH (Low) Insertion Peptide (pHLIP) helix embedded in a lipid membrane, surrounded by water molecules that are localized to the peptide. This illustrates our finding that the presence of hydrophilic residues within the sequence leads to enhanced hydration within the membrane, which we postulate to stabilize the peptide in its native conformation.
The pHLIP peptide itself is important to study as it has vast potential as a cancer diagnostic and treatment tool; pHLIP gets its name from its unique property wherein it selectively folds and inserts into cells with acidic extracellular pH. The characteristic extracellular acidity of tumor cells makes pHLIP a viable option as a selective drug or label delivery vehicle. Understanding how pHLIP interacts with and perturbs the plasma membrane is another step towards engineering the peptide as an effective therapeutic agent.
While we report this method in the context of the pHLIP, the technique detailed in the article can easily be generalized to the broader field of membrane proteins and beyond. With access to localized, dynamical information of a native system, this is a powerful tool in understanding biological complexity at a fundamental level.
More recent research from the Baiz Group at University of Texas- Austin can be viewed at www.baizgroup.org.
- Jennifer Flanagan and Carlos Baiz