Obiettivo
Posttranscriptional gene regulation is an essential process exerted by a multitude of RNA-binding proteins (RBPs) and allows for rapid adaptation of the cellular proteome to environmental perturbations. Previously, only in a limited number of instructive cases, the RNA networks targeted by individual RBPs had been elucidated. The recent proteome-wide unbiased identification of RBPs yielded a comprehensive catalogue of RBPs acting in human cells and has assigned an RNA-binding activity to over 300 orphan proteins, however without revealing their biological function. FASTKD (FAS-activated serine/threonine kinase domain-containing) proteins constitute an entire family of newly assigned RBPs with poorly defined functions and lack classical RNA binding domains. A loss of function mutation within FASTKD2 has been associated with a lethal form of infantile encephalomyopathy. FASTKD2 localizes to mitochondria and appears to regulate mitochondrial homeostasis by entirely undefined mechanisms. To address to which extent and how RNA binding contributes to the evidently vital functions of FASTKD2 I will extensively characterize the FASTKD2-RNA interface. I will determine the regions of FASTKD2 that interact with RNA making use of a novel and unprecedented technique termed RBDmap. The results of this analysis will guide systematic tests of RNA binding mutants of FASTKD2 in RNA interference based complementation assays. To obtain a comprehensive picture of the factors mediating the effects associated with a loss of function of FASTKD2 I will analyze the network of proteins and RNA motifs associating with FASTKD2 at the systems level. The models derived from the obtained data will be validated in cell-based assays. The required interdisciplinary approach is unique and will yield valuable insights into the molecular actions and interconnections of an entirely new type of RNA binding proteins in mitochondrial homeostasis in health and disease.
Campo scientifico
Argomento(i)
Invito a presentare proposte
FP7-PEOPLE-2013-IEF
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Meccanismo di finanziamento
MC-IEF - Intra-European Fellowships (IEF)Coordinatore
69117 Heidelberg
Germania