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H2020Докторантска мрежа2019–2024

UBIMOTIF · Short linear interaction motifs as specificity determinants in the ubiquitin system – discovery, mechanisms and therapeutic opportunities

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период
2019-12-01 → 2024-05-31
Финансиране от ЕС
4 143 173 €
Участници
11
Схема
MSCA-ITN

Линиите свързват координатора с партньорите.

Накратко на български

Късите линейни мотиви в протеините определят кои точно молекули ще бъдат разпознати и променени от убиквитиновата система. Разбирането на този механизъм помага при изследването на раковите забовения и разработването на нови лекарствени средства.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Short linear interaction motifs as specificity determinants in the ubiquitin system – discovery, mechanisms and therapeutic opportunities

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 are a powerful entry point for developing therapeutic agents that are able to either inhibit or hijack the ubiquitin system. The UBIMOTIF network brought together researchers in a European network focusing on SLiMs in the ubiquitin system. A unique aspect of UBIMOTIF was that it merged 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 provided an ideal training setup for the early-stage researchers as they got exposed to different disciplines. During the lifetime of UBIMOTIF the network successfully identified a large number of SLiMs experimentally and characterized these in cellular systems and using computational methods. Computational pipelines were developed that provide important tools for studying SLiMs in the future in different biological pathways. A number of ubiquitin ligases where also targeted in therapeutic strategies which allowed the identification of small molecule fragments and PROTAC scaffolds for further developments as therapeutic agents. In the network there was a strong emphasis in training the ESRs with a focus on both scientific skills and transferable skill training. Furthermore, a strong network identity was established among the ESRs through the secondments, joint training activities and participation and presentation at annual meetings.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

A major challenge is the lack of therapeutic approaches for numerous human diseases, which poses a societal challenge. The ubiquitin system is a major promising source for novel therapeutic approaches but its potential has not been fully exploited due to limited insight and lack of researchers trained in understanding and identifying avenues to target the ubiquitin system. Ubiquitin ligases and deubiquitinating enzymes (DUBs) comprises enzymes that actively add or remove ubiquitin from proteins to regulate cell physiology. How these enzymes selectively recognize their substrates is largely unknown but an emerging theme is that a globular domain in the enzyme binds a short linear interaction motif (SLiM) in the substrate. SLiMs are short peptide motifs that constitute ideal entry points for understanding the ubiquitin system as they provide detailed insight into substrate selection and how this regulates the underlying biology. Further, SLiMs provide direct routes to therapeutic exploitation as they serve as peptide scaffolds for drug development and tools to highjack the ubiquitin system. The potential of SLiMs has not been capitalized upon because a method for efficient identification was missing, interactions between relevant partners were lacking and this has hampered training of young researchers. UBIMOTIF overcomes these barriers by exploiting novel technological advances to identify SLiMs and uniting outstanding complementary researchers and industrial partners with a common vision to provide outstanding training of early career scientist in SLiMs and the ubiquitin system. The UBIMOTIF topic provides ideal training of young researchers, as it requires a multidisciplinary and intersectorial approach providing training in multiple cutting-edge technologies. The impact of UBIMOTIF will be unprecedented insight into the ubiquitin system, novel therapeutic opportunities and a skilled workforce that can fill the exhausted pipelines of European companies.

Оригинален текст от CORDIS (на английски).

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Данни: CORDIS, © Европейски съюз