Glycines are small and thus valued by evolution for their flexibility within crowded and contorted protein environments. Now, Claudia Parrini, Fabrizio Chiti (Università degli Studi di Firenze, Italy), and colleagues find another reason for conserving glycines: they can inhibit protein aggregation.

“We believe that proteins have a general tendency to aggregate into amyloid-like structures,” says Chiti. Proteins respond by covering β sheets, or including charges, bulges, or turns.

When Chiti looked at sequences of acylphosphatase (AcP), his folding workhorse, he saw another possibility. The sequences from genome projects had six glycines conserved across the three domains of life. “Glycines are very flexible,” says Chiti. “When you put a glycine into an amyloid state it has only one possible conformational shape. So this has a high entropic cost.” Theoretically this cost should be a barrier to aggregation.

The Italians tested this idea by changing each of the conserved glycines to an alanine. Two were involved in catalysis, and one mutant aggregated in bacteria. The remaining three mutants had no significant defect in either catalysis or protein stability, but they did aggregate significantly faster than the wild-type protein. Enhanced aggregation was seen even when a glycine was replaced by one of several charged residues, which should resist aggregation.

Glycines are well conserved in many proteins. Further study is needed to see whether the anti-aggregation function for glycines can be generalized.


Parrini, C., et al.