Project Details
Projekt
Characterization of the role of the NDRG3/GOSR2 complex in ER-to-Golgi transport
Subject Area
Cell Biology
Biochemistry
Biochemistry
Term
from 2014 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 262447144
SNARE [soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor] proteins play fundamental roles in Membrane trafficking in eukaryotic cells by mediating membrane fusion of vesicles with their target membrane. SNAREs contain an ex¬tended coiled-coil stretch (the SNARE motif) and form quaternary SNARE complexes that are necessary for membrane fusion. We are particular interested in Endoplasmic Reticulum (ER)-to-Golgi transport and the role of GOSR2 in this process. GOSR2 is a Q-SNARE in which we have identified mutations causing progressive myoclonus epilepsy (PME) and scoliosis. Some patients present also with congenital muscular dystrophy (CMD), suggesting a more severe impairment of GOSR2 function and point to an additional physiological role of GOSR2 in skeletal muscle. Within the last funding period, we developed a yeast-based experimental approach to test PME-causing missense mutations in GOSR2 for functionality. Furthermore, we performed molecular dynamics (MD) simulations to understand at a molecular level the impact of GOSR2 mutations on the SNARE complex. Our data suggest that a combination of yeast and in silico experiments can evaluate the functional impairment of GOSR2 thereby allowing to predict the course of disease. Our attempts to generate GOSR2 knockout mice showed embryonic lethality further suggesting that complete loss of function of GOSR2 is incompatible NDRG protein family members in regulating membrane trafficking.This project will contribute to our understanding of the physiological function of the interaction of NDRG3 and GOSR2 under normoxic and hypoxic conditions and will reveal if this interaction has an impact on GOSR2-related diseases. Furthermore, we propose that regulating SNARE complexes is a novel conserved function of NDRG Protein family members. with life. Furthermore, we have identified NDRG3 as a novel interaction partner of GOSR2. Our preliminary results suggest that this cytosolic protein controls ER-to-Golgi transport under hypoxia. Within the framework of this application, we intend to characterize the NDRG3/GOSR2 complex on a molecular level and aim to understand the physiological relevance of the interaction of NDRG3 and GOSR2. We are proposing experiments, which focus on the role of NDRG3 in modulating ER-to-Golgi transport under normoxic and hypoxic conditions and want to understand if GOSR2/NDRG3 interaction contributes to the pathophysiology of GOSR2-related disease. The following fundamental aspects will be analyzed: i) molecular characterization of the GOSR2/NDRG3 complex ii) characterization of the regulatory role of NDRG3 on ER-to-Golgi transport and iii) role of NDRG protein family members in regulating membrane trafficking. This project will contribute to our understanding of the physiological function of the interaction of NDRG3 and GOSR2 under normoxic and hypoxic conditions and will reveal if this interaction has an impact on GOSR2-related diseases. Furthermore, we propose that regulating SNARE complexes is a novel conserved function of NDRG Protein family members.
DFG Programme
Research Grants
