Fusion peptide

The major stmctural feature of the HAz chain (blue in Figure 5.20) is a hairpin loop of two a helices packed together. The second a helix is 50 amino acids long and reaches back 76 A toward the membrane. At the bottom of the stem there is a i sheet of five antiparallel strands. The central i strand is from HAi, and this is flanked on both sides by hairpin loops from HAz. About 20 residues at the amino terminal end of HAz are associated with the activity by which the vims penetrates the host cell membrane to initiate infection. This region, which is quite hydrophobic, is called the fusion peptide. 

Figure 5.27 Schematic representation of a model for the conformational change of hemagglutinin that at low pH brings the fusion peptide to the same end of the molecule as the receptor binding site. The fusion peptide (purple) is at the end of heUx A about 100 A away from the receptor binding site in the high pH form. In the low pH fragment this region of helix A has moved about 100 A towards the area where the receptor binding sites are expected to be in the intact hemagglutinin molecule. (Adapted from D. Stuart, Nature 371 19-20, 1994.)...

Mflnch J, Standker L, Adermann K, Schulz A, Schindler M, Chinnadurai R, Pdhlmann S, Chaipan C, Biet T, Peters T et al. (2007) Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 129 263-275 Nisole S, Stoye JP, Saib A (2005). TRIM family proteins retroviral restriction and antiviral defence. Nat Rev Microbiol 3 799-808... 

Gallaher WR (1987) Detection of a fusion peptide sequence in the transmembrane protein of human immunodeficiency virus. Cell 50 327-328... 

Quintana FJ, Gerber D, Kent SC, Cohen IR, Shai Y (2005) HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T cell activation. J Chn Invest 115 2149-2158 Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M, Pohlmann S, Sfakianos JN, Derdeyn CA, Blumenthal R, Hunter E, Dorns RW (2002) Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA 99 16249-16254... 

Rege, K., Patel, S.J., Megeed, Z., and Yarmush, M.L. (2007) Amphipathic peptide-based fusion peptides and immunoconjugates for the targeted ablation of prostate cancer cells. Cancer Res. 67, 6368-6375. 

Grasnick D, Sternberg U, Strandberg E, Wadhwani P, Ulrich AS (2011) Irregular structure of the HIV fusion peptide in membranes demonstrated by solid-state NMR and MD simulations Eur Biophys J 40 529-543... 

Smaller peptides are difficult to overexpress in E. coli and are additionally degraded in cells. These problems are commonly circumvented if fusion peptides are used from... 

MS analysis of the 11-mer, verified its internal sequence. Goulombe and colleagues were also able to isolate and identify the sequence of a fusion peptide between the G-terminal domain of ubiquitin and the N-terminal domain of HA-tagged p21 that also contained, downstream of the tag, a stretch of residues derived from the N-terminal domain of the native substrate, but without the iMet (which was removed during the construction of the tagged protein) [22]. 

NLS/GAL4-AD/HA epitope GRIF-1 (1-913) fusion peptide GRIF-1 (8-633) fusion peptide GRIF-1 (124-283) fusion peptide OIP106 (1-953) fusion peptide OIP106 (124-283) fusion peptide... 

Low pH of endosome triggers extension of HA fusion peptides, which insert into endosomal membrane. 

HA fusion peptide creates local disruption of bilayer, and hemifusion occurs outer monolayer of virus fuses with inner monolayer of endosome. 

Morris, K. F Gao, X. and Wong, T. C. (2004) The interactions of the HIV gp41 fusion peptides with zwitterionic membrane mimics determined by NMR spectroscopy. Biochim. Biophys. Acta 1667, 67-81. 

Hsu, S. C., Schadeck, E. B., Delmas, A., Shaw, M., and Steward, M. W. (1996), Linkage of a fusion peptide to a CTL epitope from the nucleoprotein of measles virus enables incorporation into ISCOMS and induction of CTL responses following intranasal immunization, Vaccine, 14,1159-1166. 

The structure of the HA2 N-terminal fusion peptide has been probed by a combination of NMR and electron paramagnetic resonance (EPR) in detergent micelles that mimic the lipid bilayer, at both acid and neutral pHs (Han et al, 2001). At both acidic and neutral pH the structure is predominantly helical with a kink where it rises most prominently to the presumptive membrane surface. At lower pH the kink is stronger, there is additional 3io helix, and two charged residues are rotated out of the membrane plane. The stronger kink likely allows the peptide to become more deeply immersed, perhaps disrupting the membrane and facilitating fusion. 

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