Aggregation-prone regions

Pawar AP, Dubay KF, Zurdo J, Chiti F, Vendruscolo M, Dobson CM (2005) Prediction of aggregation-prone and aggregation-susceptible regions in proteins associated with neurodegenerative diseases. J Mol Biol 350 379-392... 

Several studies have confirmed that beta-amyloid peptides undergo structural transitions to form mobile oligomers that are composed of a particular aggregation-prone conformation of the peptide. Once the oligomers exceed critical size, they nucleate to form protofilaments which finally transform to crossbeta sheets or fibrils that are responsible for the formation of extracellular amyloid plaques. The tendency to form beta-strands is due to its ability to stabilize the beta-turn by a salt bridge between residues aspartic acid-23 and lysine-28 and the hydrophobic region. 

Gross and coworkers used the bottom-up HX-FTD method to pinpoint changes in deuterium uptake for single amides in wild-t5q)e and mutant form of apolipoprotein F4 (Apo F4) [65]. Apo F4, a major risk factor for Alzheimer s and cardiovascular diseases, is prone to aggregation where the oligomerization is promoted by residues in the C-terminal region. By comparison of deuterium levels in individual amide residues in wild-type Apo F4 and a mutant that remains in its monomeric form due to the substitutions of four C-terminal residues, several residues involved in the selfassociation process of Apo F4 were identified. 

Sometimes a situation may arise when late-arriving particles are less prone to reach the central region, thereby attaching themselves at the periphery of the cluster. For analysis one uses mathematical properties, such as the number of distinct sites visited at least once in a t-step walk S the mean square displacement to monitor such processes [21]. One of the reasons for the success of DLA model is the large number of experimental systems displaying a structure similar to the DLA aggregate. A typical DLA cluster is shown in Fig. 13.9. 

With peptides that have become aggregated it is frequently not possible to obtain complete reaction, even after carrying out multiple acylation reactions. In such cases it is often necessary to repeat the synthesis, incorporating an Hmb-protected residue (Chapter 5) or an oxazolidine-dipeptide (26-28) two to four residues before the region prone to aggregation. 

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