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Humboldt-Universitaet zu Berlin - Collaborative Research Center for Theoretical Biology

Understanding the biological function of HEAT-repeat containing human proteins

HEAT repeats are tandem sequence repeats found in a large number of biologically very important proteins such as huntingtin, the protein mutated in Huntington’s chorea. There is accumulating evidence that domains formed by HEAT-repeats are important for the formation of protein-protein interactions. However, this has not been studied systematically. For example, our novel data show that domains of HEAT repeats in huntingtin drive potential intra- as well as inter-molecular associations that have never been described before.

Our objective is to study the protein complexes formed by domains of HEAT-repeats from human proteins. This will help to better understand the biological function of many proteins usually difficult to characterize when studied as a whole because of their large size and the complexity of their interactions, as it is the case of huntingtin.

We plan to extend our project based on strategies developed for the study of huntingtin during the previous funding periods. Previously, we elucidated the protein interaction network for huntingtin identifying new protein interactions and characterizing proteins with no previous functional annotation. Then we generated a large scale network of experimentally verified protein-protein interactions in humans using high-throughput Y2H assays. These data were combined with computationally derived data to generate a new database (UniHI). By integrating with gene expression data from the Huntington’s disease, we observed that CRMP1 overexpression reduces Huntingtin aggregation and toxicity, a promising step in using our data to find new targets for therapy of Huntington’s disease.

Now, our aim for the following period is to expand the methods applied to huntingtin to the study of other human proteins containing HEAT repeats. Initially, we will select a set of interesting proteins with potential HEAT repeats. Then we will predict accurately their repeats using bioinformatics tools. According to the predictions, we will clone fragments with the repeats, which are expected to form domains for protein interaction. We will then test whether those fragments participate in protein-protein interactions with systematic techniques (for example, using systematic screens with our yeast-two-hybrid libraries) and validate the results with independent assays. Finally, we will analyse the data computationally to detect individual amino acids important for the interactions, which will be investigated experimentally using amino acid replacement.

The detailed structural and experimental data about interactions of HEAT-repeat containing proteins will help us understand important biological processes and human diseases, allowing us, for example, the search for modulators of Huntington’s chorea and drugs that will have therapeutic effects on patients with this disease.

description of the 1st period german version
description of the 2nd period