期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：6
页码：1797-1802
DOI：10.1073/pnas.1415895112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMost proteins must be folded to perform their function, which typically involves binding another molecule. This property enables protein traits of stable folding and strong binding to emerge through adaptation even when the trait itself does not increase the organism's fitness. Such traits, known as evolutionary "spandrels," have been investigated across many organisms and scales of biology. Here we show that proteins can spontaneously evolve strong but nonfunctional binding interactions. Moreover, evolution of such interactions can be highly unpredictable, with chance mutation events determining the outcome. In contrast, evolution of functional interactions follows a more predictable pattern of first gaining folding stability and then losing it as the new binding function improves. Binding interactions between proteins and other molecules mediate numerous cellular processes, including metabolism, signaling, and gene regulation. These interactions often evolve in response to changes in the protein's chemical or physical environment (such as the addition of an antibiotic). Several recent studies have shown the importance of folding stability in constraining protein evolution. Here we investigate how structural coupling between folding and binding--the fact that most proteins can only bind their targets when folded--gives rise to an evolutionary coupling between the traits of folding stability and binding strength. Using a biophysical and evolutionary model, we show how these protein traits can emerge as evolutionary "spandrels" even if they do not confer an intrinsic fitness advantage. In particular, proteins can evolve strong binding interactions that have no functional role but merely serve to stabilize the protein if its misfolding is deleterious. Furthermore, such proteins may have divergent fates, evolving to bind or not bind their targets depending on random mutational events. These observations may explain the abundance of apparently nonfunctional interactions among proteins observed in high-throughput assays. In contrast, for proteins with both functional binding and deleterious misfolding, evolution may be highly predictable at the level of biophysical traits: adaptive paths are tightly constrained to first gain extra folding stability and then partially lose it as the new binding function is developed. These findings have important consequences for our understanding of how natural and engineered proteins evolve under selective pressure.
