Our laboratory consists of interacting scientists that are interested in improving our basic understanding and manipulation of interactions between proteins, using a combination of computational and experimental approaches.
This embraces different levels of resolution and scale: starting from the basic atom - level details of interactions; continuing to prediction and characterization of specific interactions; and finally addressing the ultimate question of their role within the context of a cell and a whole organism.
Our computational tools include the structure-based computational prediction and manipulation of specific interactions using the Rosetta modeling framework, analysis of evolutionary signals hidden in sequences, and large-scale integration of this data by machine-learning approaches.
A recent ERC starting grant has made it possible for us to realize this dream and to open a wet lab. Our experimental setup includes the characterization of interactions using biophysical methods such as ITC, as well as in vitro selection with Yeast surface Display. In addition, we have embarked on the journey of characterizing the functional role of proteins with repeated domains for the adaptability of yeast to environmental changes.
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Our Msc student Michal Sperber is finishing her Thesis on the structure-based identification of Geranyl-geranylation substrates.
Our Msc student Vered Fishbain-Yoskowitz has graduated - Congratulations!
Our Post-doctoral fellow Lavanya Pushpam is returning to India - we will miss you!
All the best to both!
The binding between cohesin and dockerin modules in the cellulosome presents an interesting example of a high-affinity interaction that shows binding promiscuity within the different modules in a species, but binding specificity between species.
Using a combination of computational and experimental approaches to evaluate effects of targeted point mutations at the interface (in collaboration with the Bayer lab at the Weizmann Institute), we show that this species barrier can easily be crossed.
In addition to traditional hotspot residues that contribute significantly to binding, our mutational analysis also identified a specificity hotspot residue in the cohesin module that upon mutation can either generate a promiscuous cohesin module that binds to both cognate and non-cognate dockerins, or a specificity switch that binds with strong preference to the non-cognate dockerin.
Congratulations to Dan Reshef and Michal Slutzki on their work!
Recent years have shed much light on the important role and the structural characteristics of peptide-mediated interactions. These protein interactions involve a linear short motif in one partner, bound to a (often) globular domain in the partner. Consequently, they are usually rather weak and transient, and therefore amenable to regulation.
How then are these interactions influenced by their context? In particular, many peptide binding domains, and many peptide motifs, are found in repeats. What are the integration strategies that these repeated regions use to process a signal?
In our group we study the pathways of mutual influence of WW domains. This paper presents a comprehensive overview and classification of the integration strategies that have been reported for proteins that contain more than one WW domain. Interestingly, we find that positive cooperativity for peptide binding between two adjacent WW domains is not observed: Rather, addition of a WW domain tends to reduce binding affinity of the first, suggesting that the different proteins aim at a similar overall binding affinity, achieved either by one or more interactions.