COTETHERS · Molecular characterization of vesicle tethering complexes as novel regulators of collagen trafficking
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2017-04-01 → 2019-03-31
- Финансиране от ЕС
- 168 277 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Молекулярните комплекси, които транспортират ензими като LH3, регулират правилното съзряване на колагена в клетките. Разбирането на тези процеси помага при изследването на редки генетични заболявания и разпространението на ракови метастази.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Molecular characterization of vesicle tethering complexes as novel regulators of collagen trafficking
Correct maturation of collagen molecules is critical for cellular development and physiology, and for tissue organization into functional compartments, including organs, extracellular matrix and connective tissue. In 2016, a novel pathway regulating collagen trafficking was proposed, and its essential components were identified (Figure 1). Central to this pathway are two trafficking proteins VPS33B and VIPAR (core CHEVI complex) which have been identified as primarily responsible for the trafficking of at least one enzyme responsible of collagen post-translational modifications, the lysyl- hydroxylase 3 (LH3). Genetic mutations in both the core CHEVI complex and its cargo enzyme induce rare but highly invalidating and often lethal phenotypes, characterized by abnormal collagen distribution and/or maturation often linked to impairment in endosomal trafficking. Moreover, the cargo enzyme and its human homologues, LH1 and LH2, have been found implicated in the progression of cancer metastatization. Mechanisms of LH secretion in metastatic cancers have not been identified, although we can speculate about an involvement of the CHEVI complex. In the time of this Marie Curie Individual Fellowship, I characterized the molecular players constituting the CHEVI complex and their cargo (Figure 1). I obtained structural information of the core CHEVI complex produced in mammalian cell lines, by combining small angle X-ray scattering analysis with cross-linking and native mass spectrometry (MS). In parallel, I contributed to the structural and functional characterization of its cargo LH3, combining X-ray crystallography, electron microscopy (EM), mutagenesis scanning and activity assays and expanded the study to the entire LH family. Overall, the discoveries made in the timefame of COTETHERS project represent to date an invaluable resource for the society, since they will have direct impact on treatment of highly invalidating health conditions.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Collagen maturation (through post-translational modifications, quaternary assembly and transport) is critical for tissues and organ development and homeostasis. This complex process involves numerous actors in different sub-cellular compartments, which in turn depend on highly regulated trafficking systems. Although the mechanisms of vesicular trafficking, membrane tethering and fusion are conserved throughout eukaryotic evolution, highly specialized tethering complexes have evolved to regulate specific fusion events. Recently, a novel pathway regulating collagen trafficking has been identified. Central to this pathway are two trafficking proteins, homologous to, but not part of, classical vesicle tethering components. At present, very little is known about their specific functions. Genetic mutations in both proteins induce rare but highly invalidating and often lethal phenotypes, characterized by abnormal collagen distribution, disorders of the extracellular matrix organization and impairment in endosomal trafficking. In this proposal, I will develop a multidisciplinary approach, merging cutting edge methodologies of affinity purification coupled to mass spectrometry with structural biology and biophysics to decipher the molecular mechanisms driving membrane tethering and, more broadly, endosomal trafficking, through this new complex. These results will unveil unprecedented mechanisms of vesicular trafficking, offering a potential for translational research on collagen-related diseases and also on disorders related to vesicular trafficking, possibly paving the way to future therapeutic strategies.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITA DEGLI STUDI DI PAVIA · PaviaКоординаторИталия
Връзки
Данни: CORDIS, © Европейски съюз