Computational predictions and an experimental test on proteins that link biological functions

We developed a protein-protein interaction network analysis method to find the proteins which serve as links between cell cycle, cytokinesis and polarized cell growth regulation in fission yeast cells and experimentally verified the method on one of the predicted proteins.

HFSP Young Investigator Grant holders Attila Csikász-Nagy, Rafael Carazo-Salas and Masamitsu Sato and colleagues
authored on Thu, 03 January 2013

Rod shaped fission yeast cells grow in a polarized fashion and relocalize their growth machinery several times during the cell cycle. Somehow the cell cycle regulatory network controls the growth at both tips of the cell and later relocates the growth machinery to the middle of the cell to induce cell division. The exact details of this coupling are unknown. We investigated the proteins that are important to channel signals between the cell cycle, cell division and growth machineries to synchronize these processes in time. We analyzed the protein-protein interaction network of the proteins functionally annotated to these biological functions and developed a new network measure that can identify the proteins that link biological processes. This new network measure, “linkerity”, was predicting Sts5 as a possible linker between polarized cell growth and cell cycle regulation. Sts5 was originally identified as a cell polarity regulator, but here we showed that its localization is cell cycle regulated, and thus it could serve as a bridge between cell cycle and cell polarity regulation.

Our results suggest that in fission yeast the stress signaling pathway might stand between cell cycle and cell polarity regulation. The network analysis technique we developed can be used to investigate coupling between any biological functions in any organisms where enough data on protein-protein interactions are available. Indeed, our work is the first extensive network analysis using fission yeast data, as earlier efforts were focusing only on model organisms with much richer experimental data. We have shown that network analysis can give reliable results and successful predictions even on a less characterized organism.

Figure: The concept of linkerity. In a hypothetical protein-protein interaction network (top) we look for proteins which are associated with a given list of Gene Ontology (GO) biological function terms - with some proteins associated to more than one term (middle).  Linkerity identifies the proteins that are at the edge of a sub-network, but are central in the full network (top linkerity proteins from the red sub-network are numbered by their ranking on the bottom panel). The concept holds for any network, where network topology independent sub-networks can be defined.

Reference

Linkers of cell polarity and cell cycle regulation in the fission yeast protein interaction network. Vaggi F, Dodgson J, Bajpai A, Chessel A, Jordán F, Sato M, Carazo-Salas RE, Csikász-Nagy A. PLoS Comput Biol. 2012 Oct;8(10):e1002732. doi: 10.1371/journal.pcbi.1002732.

Pubmed link

Open access PLOS link