BIOCHEMISTRY: Mutate and Aggregate

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Science  01 Feb 2002:
Vol. 295, Issue 5556, pp. 769c
DOI: 10.1126/science.295.5556.769c

In fully folded proteins, hydrophobic amino acids are hidden in the protein core. But when a protein is unfolded or partially folded, these residues render it prone to aggregation.

Chiti et al. now provide much-needed insights into the molecular basis of aggregate formation. They introduced point mutations in the protein acylphosphatase (AcP) and determined the relative aggregation rates of the mutants. Mutations in two particular regions of the protein, which possess high hydrophobicity and propensity to form β-sheet structure, led to increased rates of aggregate formation. Mutational “hot spots” in protein misfolding diseases may thus result from changes in the aggregation behavior.

The regions determining the aggregation rate are distinct from those that determine protein folding. Only a small number of residues is involved in setting the scene for aggregation, raising the hope that aggregation is governed by relatively simple principles. — JU

Nature Struct. Biol.10.1038/nsb752.

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