Peptide fibril-forming

An alternative to modifying the functional group attached to fibrils is to utilise the chemistry present in the amino acid side chains. Furthermore, as peptides often undergo specific modification by enzymes in vivo, these could be harnessed for synthetic purposes. Qll (Ac-QQKFQFQFEQQ-Am, a fibril-forming peptide based on Pi 1-2), was coupled to lysine-based molecules by treatment with an enzyme (tissue transglutaminase, TGase) which results in a reaction between lysine and glutamine side chains [72] (Fig. 32). 

Baneqee A, Das AK, Drew MGN, Baneqee A. Supramolecular parallel 8-sheet and amyloidlike fibril forming peptides using S-aminovaleric acid residue. Tetrahedron 2005 61 5906-5914. 

Thioflavin binding indicated fibrils formed for two of these three mixtures (EEEK, EKEE, KKKK and EEKE, KEEE, KKKK). The requirement of all three peptides to produce fibrils was further demonstrated by testing individual peptides... 

Protein structures are so diverse that it is sometimes difficult to assign them unambiguously to particular structural classes. Such borderline cases are, in fact, useful in that they mandate precise definition of the structural classes. In the present context, several proteins have been called //-helical although, in a strict sense, they do not fit the definitions of //-helices or //-solenoids. For example, Perutz et al. (2002) proposed a water-filled nanotube model for amyloid fibrils formed as polymers of the Asp2Glni5Lys2 peptide. This model has been called //-helical (Kishimoto et al., 2004 Merlino et al., 2006), but it differs from known //-helices in that (i) it has circular coils formed by uniform deformation of the peptide //-conformation with no turns or linear //-strands, as are usually observed in //-solenoids and (ii) it envisages a tubular structure with a water-filled axial lumen instead of the water-excluding core with tightly packed side chains that is characteristic of //-solenoids. 

Fig. 1. Structure of amyloid fibrils formed by the human amylin peptide. Negatively stained (A) and metal shadowed (B) fibrils formed by human amylin (adapted from Goldsbury et al., 2000a). (C) A human amylin fibril model formed by three protofibrils having a superpleated /i-structure (adapted from Kajava et al., 2005). Only Ca traces of the polypeptide chains are shown. (D) Atomic model of the cross-/ motif formed by the human amylin peptide (adapted from Kajava et al, 2005). Scale bar, 100 nm (A and B).

Jones, S., Manning, J., Kad, N. M., and Radford, S. E. (2003). Amyloid-forming peptides from beta2-microglobulin-Insights into the mechanism of fibril formation in vitro. J. Mol. Biol. 325, 249-257. 

Petkova, A. T., Buntkowsky, G., Dyda, F., Leapman, R. D., Yau, W. M., and Tycko, R. (2004). Solid state NMR reveals a pH-dependent antiparallel beta-sheet registry in fibrils formed by a beta-amyloid peptide./. Mol. Biol. 335, 247-260. 

Melnik TN, Villard V, Vasiliev V, Corradin G, Kajava AV, Potekhin SA. Shift of fibril-forming ability of the designed a-helical coiled-coil peptides into the physiological pH region. Protein Eng 2003 16 1125-1130. 

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