College of Liberal Arts & Sciences

Global view of the protein universe

Friday, April 8, 2016

Friday, April 8, 2016
2:00 pm, MRB 200 Conference Room

Dr. Nir Ben-Tal

Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University

Global view of the protein universe§

§ Joint work with Rachel Kolodny and Sergey Nepomnyachiy

How are proteins related to each other? Which physicochemical considerations affect protein evolution, and how? Forming a global picture of the protein universe can help address these, and similar, questions. However, this is difficult to do because we have to piece the global picture from many local details: comparisons of pairs of protein structures./p>

Conveniently, proteins are made of various combinations of repeating structural domains (e.g., the two structures at the center of the figure); it is therefore sufficient to analyze the relationships among these. We study the evolutionary relationships among a representative set of 9,710 domains. We compare all-against-all domains, searching for repeating elongated amino acid segments, referred to as motifs; for example, the cyan segment shared between the two domains at the center of the figure. These motifs have similar sequence and structure, and can therefore indicate an evolutionary relationship among the proteins. The results are presented as a series of networks, in which edges connect domains that share a motif (see figure).

Using reasonable similarity thresholds, the network manifests a large connected component, as well as many isolated ‘islands’, revealing the complex nature of protein space, which includes continuous and discrete regions. This feature does not strongly depend on the criteria used to define similarity; excluding the results obtained using extremely strict (figure, bottom left) or lax (upper left, near the end of the arrow) similarity thresholds. The network can also be interpreted as a collection of evolutionary paths in protein space. Paths in the major connected component of the network include many domains, and demonstrate the sequence and structural resemblance between them. The large amount of paths within the major connected component suggests that it is particularly easy to add and delete motifs in the continuous region of protein space without impeding structural stability. Apparently, evolution took advantage of this property to design new proteins with novel functions.

This is the first study that combines sequence and structural similarity between proteins within the context of networks to provide a bird's eye view of the protein universe. The network offers a natural way to organize and search in protein space. It could be used to theorize about protein evolution, suggest evolutionary pathways between domains, and hence maybe suggest strategies for protein design.

To read more: Sergey Nepomnyachiy, Nir Ben-Tal* and Rachel Kolodny*.universe. PNAS 111: 1691–11696 (*Co-corresponding authors)

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