Understanding the Role of Peptide-Lipid Reactions in Biological Systems

Abstract

The field of reactions in lipid membranes, so called intra-membrane reactions, has thus far been limited by the sensitivity and availability of analytical techniques suitable for their study. Use of LCMS with a high performance FTICR mass analyser has opened up this field of complex reactions dramatically, revealing in particular the existence of a novel intra-membrane reaction, intrinsic lipidation. Intrinsic lipidation describes transfer of the acyl chain of a membrane phospholipid onto the nucleophile of a membrane active peptide, such as melittin. Unlike post-translational peptide lipidation, intrinsic lipidation in the membrane proceeds without the aid of an enzyme. Identified as a process generic to membrane active peptides in vitro, intrinsic lipidation has been implicated in several antimicrobial and disease-related contexts, not least as a potential mechanism for amyloid plaque formation in Alzheimer's and other amyloid-related degenerative diseases. Further, promising early results suggest intrinsic lipidation takes place in vivo, playing a role in the modification of natural protein aquaporin-0. Whilst the impact of lipidation on this protein is currently poorly understood, it does signify a potentially novel means of drug targeting. Focus is now upon conclusively confirming the role of intrinsic lipidation in both natural systems and in disease-related contexts. Further, by probing factors associated with the reactivity of intrinsic lipidation it is hoped that a heightened understanding of the reaction will be reached, allowing manipulation of the reaction for drug design and disease prevention. Our most recent data on peptide and protein lipidation are presented.