Analysis of disease-related polypeptide sequences: Intrinsically unstructured proteins

Analysis of disease-related polypeptide sequences: Intrinsically unstructured proteins


Amyloid-β-protein
The most abundant forms found in amyloid plaques are a 40-mer (Aβ40) and a 42-mer (Aβ42). Although less abundant, Aβ42 is more amyloidogenic than Aβ40 and is the major component of neuritic plaques. Two main regions with high aggregation propensity can be distinguished in the aggregation profile for this polypeptide. The second region arises from the contribution of two sequence stretches comprising residues 30–36 and 38–42, respectively.

key residues: 16-21 (located in the core of Aβ fibrils)

A short 7 residues fragment comprising residues 16–22 is able to form ordered amyloid fibrils and, more interestingly, 16-LVAFF-20 and derived peptides have been shown to bind to Aβ42 and act as potent inhibitors of amyloid formation.


Islet amyloid polypeptide
Beta-cell failure in type II diabetes correlates with the formation of pancreatic islet amyloid. Islet amyloid polypeptide (IAPP, amylin), the major component of islet amyloid, is co-secreted with insulin from beta-cells.
In type II diabetes, this peptide aggregates to form amyloid fibrils that are toxic to beta-cells [26]. IAPP is an unstructured peptide hormone of 37 amino acid residues. Two "hot spots" of aggregation comprising residues 12–18 and 22–28 are detected for this peptide.
Interestingly enough, a 8–37 IAPP-fragment including both "hot spots", has been shown to form amyloid fibrils under physiological conditions.
Residues 12–17 and 22–27 are proposed to form the inner β-sheets in the fibril protofilament structure. According to this hypothesis, peptides corresponding to residues 8–20, 10–19, 20–29 of human IAPP, which include one of the "hot spots" described here, all form amyloid.
Smaller peptides derived from these regions have also been shown to form amyloid, and a recent investigation suggests that the minimal amyloid forming fragment of IAPP consists of residues 22–27. This hexapeptide fragment, NFGAIL, forms β-sheet-containing fibrils that coil around each other in typical amyloid fibril morphology.

proposed mechanisms:
- increased production and secretion of IAPP associated with increased demand for insulin might result in accumulation and aggregation of IAPP.

- impaired processing of the IAPP precursor molecule, proIAPP, by islet betacells may lead to hypersecretion of unprocessed or partially processed forms of proIAPP that may have a higher tendency for aggregation compared to mature IAPP


α-Synuclein
Several large aggregation-prone stretches were predicted for the α-Synuclein sequence: region 1–18, region 27–56 and specially region 61–94. A peptide comprising residues 68–78 of α-synuclein has been shown to be the minimum fragment that, like α-synuclein itself, forms amyloid fibrils and exhibits toxicity towards cells in culture. This fragment is included in the region 62–80 which we predict as the sequence stretch with the highest aggregation propensity. All the α-synucleinopathies are characterized by the accumulation of the 35 residues NAC fragment in the insoluble deposits. [NAC= non-Aβ component, amino acids 61–95]


(src)