In Genetic Decision Making, Proteins Learn to Listen to Each Other

Summary: Researchers have a new perspective on how certain proteins are evolving.

Source: Yale.

Genes are regulated because they need to be. Factors that determine their transcription don’t tend to change, mainly because they have so many specific jobs to do. When scientists intervene in such complex and regimented structures, they tend to break things, creating a mess and making the results hard to understand.

Working with colleagues at the Systems Biology Institute, Gunter Wagner, Professor of Ecology and Evolutionary Biology, and of Obstetrics, Gynecology and Reproductive Sciences has found examples where transcription factors actually change in evolution in spite of their many roles they play.

From their labs on West Campus, the scientists have developed a new perspective on how certain proteins are evolving.

Focusing on the interaction between two proteins, HOXA11 and FOX01, the scientists had previously shown co-dependence in the transcription of mammalian uterine cells. Published in the journal Cell Reports, they recently discovered evolutionary change where the proteins were acting as if to “decide” to become active depending on their physical interaction. This “functional cooperativity” has evolved in step with mammalian pregnancy, with certain proteins playing a role in placental mammals that can’t be found in non-placental mammals.

“When left alone, these proteins inhibit gene expression, but we know they also have the tools to activate target genes,” explains Wagner. Scientists had previously understood this “negative regulation”, assuming that transcription factors in evolution are acting mostly alone.

Image shows DNA, a pregnant woman and a kangaroo.

Focusing on the interaction between two proteins, HOXA11 and FOX01, the scientists had previously shown co-dependence in the transcription of mammalian uterine cells. NeuroscienceNews.com image is adapted from the Yale press release.

“Our recent work actually shows that the proteins evolve to actively listen to each other,” continues Wagner. “It is typical to see strong binding between the proteins, but what we have found is really the evolution of a form of directional communication.”

Wagner and his colleagues are, in effect, solving the puzzle of how these highly functioning proteins have learnt new tricks in spite of all the other things they do. Their discoveries lend new insight to pharmacology and the study of fertility and endometriosis, and for female reproductive biology in general.

About this genetics research article

Funding: Supported in part by NIDDK Grants 5R01DK088796 (SKS) and DK 32346 (SKS).

Source: Yale
Image Source: This NeuroscienceNews.com image is adapted from the Yale press release.
Original Research: Full open access research for “A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1” by Mauris C. Nnamani, Soumya Ganguly, Eric M. Erkenbrack, Vincent J. Lynch, Laura S. Mizoue, Yingchun Tong, Heather L. Darling, Monika Fuxreiter, Jens Meiler, and Günter P. Wagner in Cell Reports. Published online April 28 2016 doi:10.1016/j.celrep.2016.04.088

Cite This NeuroscienceNews.com Article
Yale. “In Genetic Decision Making, Proteins Learn to Listen to Each Other.” NeuroscienceNews. NeuroscienceNews, 29 May 2016.
<http://neurosciencenews.com/genetics-proteins-decision-4340/>.
Yale. (2016, May 29). In Genetic Decision Making, Proteins Learn to Listen to Each Other. NeuroscienceNews. Retrieved May 29, 2016 from http://neurosciencenews.com/genetics-proteins-decision-4340/
Yale. “In Genetic Decision Making, Proteins Learn to Listen to Each Other.” http://neurosciencenews.com/genetics-proteins-decision-4340/ (accessed May 29, 2016).

Abstract

A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1

Highlights
•The HOXA11 protein has a regulatory motif that masks its activation domain
•In placental mammals, upon binding to FOXO1, HOXA11 unmasks its activation domain
•In the ancestral HOXA11, binding to FOXO1 does not unmask the activation domain
•In placental mammals the HOXA11::FOXO1 complex evolved a neo-allosteric switch

Summary
Transcription factors (TFs) play multiple roles in development. Given this multifunctionality, it has been assumed that TFs are evolutionarily highly constrained. Here, we investigate the molecular mechanisms for the origin of a derived functional interaction between two TFs, HOXA11 and FOXO1. We have previously shown that the regulatory role of HOXA11 in mammalian endometrial stromal cells requires interaction with FOXO1, and that the physical interaction between these proteins evolved before their functional cooperativity. Here, we demonstrate that the derived functional cooperativity between HOXA11 and FOXO1 is due to derived allosteric regulation of HOXA11 by FOXO1. This study shows that TF function can evolve through changes affecting the functional output of a pre-existing protein complex.

“A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1” by Mauris C. Nnamani, Soumya Ganguly, Eric M. Erkenbrack, Vincent J. Lynch, Laura S. Mizoue, Yingchun Tong, Heather L. Darling, Monika Fuxreiter, Jens Meiler, and Günter P. Wagner in Cell Reports. Published online April 28 2016 doi:10.1016/j.celrep.2016.04.088

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