The CFTR-derived peptides as a model of sequence-specific protein aggregation.
Protein aggregation is a hallmark of a growing group of pathologies known as conformational diseases. Although many native or mutated proteins are able to form aggregates, the exact amino acid sequences involved in the process of aggregation are known only in a few cases. Hence, there is a need for different model systems to expand our knowledge in this area. The so-called ag region was previously found to cause the aggregation of the C-terminal fragment of the cystic fibrosis transmembrane conductance regulator (CFTR). To investigate whether this specific amino acid sequence is able to induce protein aggregation irrespective of the amino acid context, we altered its position within the CFTR-derived C-terminal peptide and analyzed the localization of such modified peptides in transfected mammalian cells. Insertion of the ag region into a different amino acid background affected not only the overall level of intracellular protein aggregation, but also the morphology and subcellular localization of aggregates, suggesting that sequences other than the ag region can substantially influence the peptide's behavior. Also, the introduction of a short dipeptide (His-Arg) motif, a crucial component of the ag region, into different locations within the C-terminus of CFTR lead to changes in the aggregation pattern that were less striking, although still statistically significant. Thus, our results indicate that even subtle alterations within the aggregating peptide can affect many different aspects of the aggregation process.
Bąk
Daniel
D
Laboratory of Cell Biology, Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211, Warsaw, Poland. dbak@imid.med.pl
Cutting
Garry R
GR
Milewski
Michał
M
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D020836:Protein Structure, Quaternary
D010455:Peptides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator