Disulfide-Bond Reshuffling in the Evolution of an Ape Placental Ribonuclease

    loading  Checking for direct PDF access through Ovid

Abstract

Disulfide bonds play important roles in the folding and stability of proteins and are evolutionarily conserved. A classic example is RNase A (also known as bovine pancreatic ribonuclease), which contains 4 conserved disulfide bonds among 8 cysteines. However, human RNase 8, a paralog of RNase A uniquely expressed in the placenta, has lost one of the conserved cysteines but gained another, when compared with RNase 8 of various monkeys and with RNase A. We here show that both the loss and gain of the cysteines in human RNase 8 occurred in the common ancestor of African great apes (humans, chimps, and gorillas) 7–13 MYA. Computational predictions suggest changes of disulfide bonding by these cysteine substitutions. Site-directed mutagenesis indicates that if the ribonucleolytic activity is essential for RNase 8's function, the gain of the cysteine must have preceded the loss. Human RNase 8 represents one of the first examples in which the presumable evolutionary change of a disulfide bond involves 1 loss and 1 gain of cysteine, instead of 2 losses or 2 gains. Our results provide the foundation for detailed analysis toward understanding the impact of disulfide-bond reshuffling on the structure, function, and evolution of proteins in general and human RNase 8 in particular.

Related Topics

    loading  Loading Related Articles