P-amyloid polypeptide

Structural Characterization of Oligomer-Aggregates of P-Amyloid Polypeptide 319... 

P-Amyloid Polypeptide Using Ion Mobility Mass Spectrometry. 313... 

Higham, C. E., Jaikaran, E. T., Fraser, P. E., Gross, M., and Clark, A. (2000). Preparation of synthetic human islet amyloid polypeptide (LAPP) in a stable conformation to enable study of conversion to amyloid-like fibrils. FEBS Lett. 470, 55-60. 

In this review, we will discuss the aggregation of three intrinsically unstructured peptides and proteins and the diseases to which they contribute. Specifically we wiU concentrate on amyloid-P (A ), islet amyloid polypeptide (LAPP), and a-synuclein. 

Marek, R, Abedini, A., Song, B. B., Kanungo, M., Johnson, M. E., Gupta, R., Zaman, W, Wong, S. S., and Raleigh, D. P. 2007. Aromatic interactions are not required for amyloid fibril formation by islet amyloid polypeptide but do influence the rate of fibril formation and fibril morphology. Biochemistry 46,3255-3261. 

Suh s group also developed several [Co (cyclen)]-based complexes for cleavage of p-amyloid 1-42 (AP42) oligomers, a possible etiology of Alzheimer disease, and human islet amyloid polypeptide (h-IAPP, also known as amylin), a cause of type 2 diabetes, typically at pH 7.5 and 37°C [95-99]. The stable Co complexes... 

Figure 18.7 FM-AFM images of lAPP fibrils on mica in PBS solution, (a) 800 nm x 800 nm, A/ = —55 Hz, tip velocity = 1 p,m/s. (b) 10 nm x 10 nm, A/ = +50 Hz, tip velocity = 195 nm/s. (c) Schematic model of the /i-strands. Abbreviations-. lAPP, islet amyloid polypeptide PBS, phosphate buffer solution.

Progress in deducing more structural details of these fibers has instead been achieved using NMR, electron microscopy and electron diffraction. These studies reveal that the fibers contain small microcrystals of ordered regions of the polypeptide chains interspersed in a matrix of less ordered or disordered regions of the chains (Eigure 14.9). The microcrystals comprise about 30% of the protein in the fibers, are arranged in p sheets, are 70 to 100 nanometers in size, and contain trace amounts of calcium ions. It is not yet established if the p sheets are planar or twisted as proposed for the amyloid fibril discussed in the previous section. 

These results indicate that is it possible to change the fold of a protein by changing a restricted set of residues. They also confirm the validity of the rules for stability of helical folds that have been obtained by analysis of experimentally determined protein structures. One obvious impliction of this work is that it might be possible, by just changing a few residues in Janus, to design a mutant that flip-flops between a helical and p sheet structures. Such a polypeptide would be a very interesting model system for prions and other amyloid proteins. 

The sustained attractiveness of photolabeling is apparent from its prominence in studies of y-secretase, an intramembrane protease that contributes to forming amyloid-p peptides and is a major target in Alzheimer s disease [60-62]. y-Secretase is a complex of at least four different polypeptides, and is difficult to engage with high-resolution structural methods. However, in a case of this kind that involves a known target, immunodetection of proteins can often specify the target of y-secretase inhibitor photoaffinity probes such as 19, and proteomic mass spectrometry is not needed. 

McPhie, P. (2004). CD studies on films of amyloid proteins and polypeptides Quantitative g-factor analysis indicates a common folding motif. Biopolymers 75, 140-147. 

Westermark, P. (2005). Aspects on human amyloid forms and their fibril polypeptides. FEBSJ. 272, 5942-5949. 

What is the nature of the insoluble forms of the prion protein They are hard to study because of the extreme insolubility, but the conversion of a helix to (3 sheet seems to be fundamental to the process and has been confirmed for the yeast prion by X-ray diffraction.11 It has been known since the 1950s that many soluble a-helix-rich proteins can be transformed easily into a fibrillar form in which the polypeptide chains are thought to form a P sheet. The chains are probably folded into hairpin loops that form an antiparallel P sheet (see Fig. 2-ll).ii-11 For example, by heating at pH 2 insulin can be converted to fibrils, whose polarized infrared spectrum (Fig. 23-3A) indicates a cross-P structure with strands lying perpendicular to the fibril axis >mm Many other proteins are also able to undergo similar transformation. Most biophysical evidence is consistent with the cross-P structure for the fibrils, which typically have diameters of 7-12 rnn."-11 These may be formed by association of thinner 2 to 5 nm fibrils.00 However, P-helical structures have been proposed for some amyloid fibrils 3 and polyproline II helices for others. 1 11... 

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