Skip to main content

Self-Perpetuating Structural States in Biology, Disease, and Genetics (2002) / Chapter Skim
Currently Skimming:

Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases
Pages 43-50

The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.


From page 43...
... It is increasingly recognized that the ability to form amyloid fibrils is not a property restricted to the relatively few amino acid sequences associated with specific diseases but is a generic phenomenon of polypeptide chains (13~. A considerable number of proteins, including several that adopt cr-helical structures under native conditions such as myoglobin and cytochrome cs52, have been shown to form amyloid fibrils in vitro, provided appropriate conditions are selected (14-17~.
Read the entire page →
From page 44...
... Monitoring the first steps in the aggregation process leading to formation of prefibrillar aggregates is gaining in importance, because it is increasingly recognized that low-molecular weight oligomers that precede formation of mature amyloid fibrils, often referred to as protofibrils, represent the fundamental pathogenic species in at least many of the amyloid diseases (11, 18, 31-33~. In our initial studies of AcP, the propensity to form fibrils was investigated for a series of mutants under conditions in which the native states of the various protein variants were substantially populated, although significantly destabilized (26~.
Read the entire page →
From page 45...
... Through analysis of the 15 mutational variants selected here, we have therefore endeavored to relate effects on the aggregation process resulting from mutations simply to the changes in the charge state of the protein at the mutated position by minimizing mutational changes of hydrophobicity and secondary structural propensity of the protein. The conformational stabilities of all of the 15 AcP variants were evaluated by means of equilibrium urea denaturation measurements (Fig.
Read the entire page →
From page 46...
... This procedure permits any change in aggregation rate to be attributed entirely to the intrinsic effect of the amino acid substitutions on the aggregation process, without the complica tions of additional contributions arising from the destabilization of the native state.
Read the entire page →
From page 47...
... Unlike the amino acid replacements that alter the hydrophobicity, or-helical or 13-sheet propensities of the AcP sequence, mutations that modify the charge of the protein are able to alter the aggregation rate even when these modifications occur outside the regions of sequence 16-31 and 87-98 that appear to be primarily responsible for regulating the aggregation process. Different regions may play a critical role at different stages of the aggregation process and therefore produce a change in the aggregation rate when mutated.
Read the entire page →
From page 48...
... The conclusion from the present study raises the possibility that some diseaseassociated mutations act primarily through a reduction of the net charge of the corresponding peptides or proteins. To explore this possibility, we have examined pathogenic mutations involving substitution, or introduction, of charged residues within the proteins or peptides associated with amyloid diseases, and for which the causative link with the pathogenic effects is not yet established.
Read the entire page →
From page 49...
... Such an approach may reveal common features in the process of protein aggregation in a particularly straightforward manner. The studies carried out on AcP show that mutations can favor aggregation either by destabilizing the native state, hence allowing unfolded or partially unfolded species prone to aggregation to be significantly populated, or by directly favoring the process of self-assembly through an increase in hydrophobicity, 1..Kelly, J
Read the entire page →
From page 50...
... 36. Booth, D
Read the entire page →

Key Terms

  • native state
  • charged residues
  • amino acid
  • aggregation rate
  • amyloid diseases

  • amyloid fibrils
  • aggregation process
  • protein aggregation
  • positively charged
  • acid substitutions

  • form amyloid
  • frontotemporal dementia
  • aggregation rates
  • protein variants
  • hereditary renal

  • acid replacements
  • acp variants
  • familial amyloid
  • polypeptide chains
  • prion protein

  • renal amyloidosis
  • charge state
  • mutations involving
  • acetate buffer
  • negatively charged

  • amyloid deposition
  • secondary structural
  • amyloid formation
  • electrostatic interactions
  • globular proteins


    • This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
    More information on Chapter Skim is available.