WHAT STUDIES OF FUSION PEPTIDES TELL US ABOUT VIRAL ENVELOPE GLYCOPROTEIN-MEDIATED MEMBRANE-FUSION

This review describes the numerous and innovative methods used to stud y the structure and function of viral fusion peptides. The systems stu died include both intact fusion proteins and synthetic peptides intera cting with model membranes. The strategies and methods include dissect ing the fusion process into intermediate stages, comparing the effects of sequence mutations, electrophysiological patch clamp methods, hydr ophobic photolabelling, video microscopy of the redistribution of both aqueous and lipophilic fluorescent probes between cells, standard opt ical spectroscopy of peptides in solution (circular dichroism and fluo rescence) and attenuated total reflection-Fourier transform infrared s pectroscopy of peptides bound to planar bilayers. Although the goal of a detailed picture of the fusion pore has not been achieved for any o f the intermediate stages, important properties useful for constrainin g the development of models are emerging. For example, the presence of alpha-helical structure in at least part of the fusion peptide is str ongly correlated with activity; whereas, beta-structure tends to be le ss prevalent, associated with non-native experimental conditions, and more related to vesicle aggregation than fusion. The specific angle of insertion of the peptides into the membrane plane is also found to be an important characteristic for the fusion process. A shallow penetra tion, extending only to the central aliphatic core region, is likely r esponsible for the destabilization of the lipids required for coalesce nce of the apposing membranes and fusion. The functional role of the f usion peptides (which tend to be either nonpolar or aliphatic) is then to bind to and dehydrate the outer bilayers at a localized site; and thus reduce the energy barrier for the formation of highly curved, lip idic 'stalk' intermediates. In addition, the importance of the formati on of specific, 'higher-order' fusion peptide complexes has also been shown. Recent crystallographic structures of core domains of two more fusion proteins (in addition to influenza haemagglutinin) has greatly facilitated the development of prototypic models of the fusion site. T his latter effort will undoubtedly benefit from the insights and const raints gained from the studies of fusion peptides.