Periodic Reporting for period 1 - UBIMOTIF (Short linear interaction motifs as specificity determinants in the ubiquitin system – discovery, mechanisms and therapeutic opportunities)
Période du rapport: 2019-12-01 au 2021-11-30
The proliferation of cells and the regulation of cellular signaling relies on the proper control of protein function. A major regulatory mechanism of protein function is the ubiquitin system that can add or remove a small ubiquitin molecule to specific proteins. A major obstacle in understanding the ubiquitin system is how specific proteins are recognized by components of the system. An emerging theme is that short linear motifs (SLiMs) which are present in proteins are recognized by the ubiquitin system. However, identification of SLiMs and how they confer specificity is largely unexplored. Uncovering this will provide fundamental biological understanding of cell regulation and its deregulation in human malignancies. Furthermore, SLiMs is a powerful entry point for developing therapeutic agents that are able to either inhibit or hijack the ubiquitin system. The UBIMOTIF network is bringing together researchers in a European network focusing on SLiMs in the ubiquitin system. A unique aspect of UBIMOTIF is that it merges researchers with expertise in SLiMs, the ubiquitin system and therapeutic approaches to allow breakthrough discoveries in the ubiquitin system. This diversity in experimental and knowledge background also provides an ideal training setup for the early-stage researchers as they will be exposed to different disciplines. The ambition of UBIMOTIF is to develop a long-lasting European network focusing on SLiMs in the ubiquitin system that can provide fundamental tools and knowledge for novel therapeutics targeting human malignancies. This collectively will contribute to a strong knowledge based European economy.
The current period has focused on recruitment of early career researchers (ESRs) to the individual projects and their training in the host environment. An infrastructure in terms of monthly journal clubs as well as transferable skills training covering among other computational approaches has been established to ensure high level training. Several ESRs have also conducted secondments in other labs in the network to expand on their technical expertise and obtain results for their projects. Focus has also been on developing a strong network environment where researchers are freely exchanging data an ideas to drive scientific discoveries beyond state of the art.
At a scientific level the work is distributed to three scientific work packages each with their unique focus on specific aspects in the ubiquitin system. One work package is using a unique SLiM discovery tool allowing large scale discovery of these and integrating this with bioinformatic approaches as well as mass spectrometry-based approaches. This has already led to the discovery of numerous novel SLiMs that is currently being validated and analysed in cell based assays. The efforts of the network have already dramatically expanded on the knowledge of SLiMs in the ubiquitin system. A web portal allowing easy access to the SLiMs discovered is established ensuring efficient data sharing within the network. This web portal also allows for future sharing of the data with the wider scientific community. Unique computational approaches has also been developed by the network to understand how SLiMs interact with their binding partner.
To harness the new knowledge of SLiMs for therapeutic approaches several projects focus on small molecule development. Promising targets for this have been identified through the efforts in the network and protein purification and screening approaches have been established. The SLiMs already identified serves as important tools for specificity in screening assays of small molecules and subsequent on target validation. To identify small molecules and PROTACS the network groups are employing fragment-based screening approaches to identify hit compounds that can be further developed.
A large effort of the network is also to understand the cellular functions of SLiMs in the ubiquitin system. A large part of the period has been on developing specific assays and tools for the ubiquitin components under investigation that is required for subsequent experiments. This has already revealed novel insights into an important cellular ubiquitin ligase and expanded on the substrate scope of numerous enzymes. Ongoing efforts focuses on validation studies in cells and integrating this with high throughput approaches profiling protein stability.
At a scientific level the work is distributed to three scientific work packages each with their unique focus on specific aspects in the ubiquitin system. One work package is using a unique SLiM discovery tool allowing large scale discovery of these and integrating this with bioinformatic approaches as well as mass spectrometry-based approaches. This has already led to the discovery of numerous novel SLiMs that is currently being validated and analysed in cell based assays. The efforts of the network have already dramatically expanded on the knowledge of SLiMs in the ubiquitin system. A web portal allowing easy access to the SLiMs discovered is established ensuring efficient data sharing within the network. This web portal also allows for future sharing of the data with the wider scientific community. Unique computational approaches has also been developed by the network to understand how SLiMs interact with their binding partner.
To harness the new knowledge of SLiMs for therapeutic approaches several projects focus on small molecule development. Promising targets for this have been identified through the efforts in the network and protein purification and screening approaches have been established. The SLiMs already identified serves as important tools for specificity in screening assays of small molecules and subsequent on target validation. To identify small molecules and PROTACS the network groups are employing fragment-based screening approaches to identify hit compounds that can be further developed.
A large effort of the network is also to understand the cellular functions of SLiMs in the ubiquitin system. A large part of the period has been on developing specific assays and tools for the ubiquitin components under investigation that is required for subsequent experiments. This has already revealed novel insights into an important cellular ubiquitin ligase and expanded on the substrate scope of numerous enzymes. Ongoing efforts focuses on validation studies in cells and integrating this with high throughput approaches profiling protein stability.
The network has used its unique screening approach to uncover new SLiMs in the ubiquitin system to move our understanding of specificity determinants beyond state of the art. This is giving the network an opportunity to obtain system wide understanding of the enzymes in the ubiquitin system. The developed computational tools are also moving our understanding of SLiM based interactions beyond state of the art and provides important tools for future biological and drug-based approaches. Integrating the results of the network with disease mutation information publicly available will pave the way for a better understanding of human disease and therapeutic targeting of these. This will thus have societal implications as it can lead to better and focused treatments of specific human diseases. The efforts of the network in developing small molecules targeting the ubiquitin system is expected to have a wider societal impact as it can lead to new treatments for human diseases which can support the growth of the European economy. Finally, the training of highly skilled researchers is essential for supporting a knowledge based European economy and the unique training the network provides to the ESRs is supporting this.