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Title: Structural biology of the PRELI-TRIAP1 mitochondrial lipid transport system
Author: Miliara, Xeni
ISNI:       0000 0004 6348 5439
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Mitochondria are involved in major cellular functions including energy production, phospholipid metabolism, stress responses and apoptosis, which are ultimately interconnected to provide cellular sustainability. Subsequently, deficiencies in mitochondrial functions are implicated in a plethora of pathological conditions including metabolic disorders, neurodegenerative disease and cancer, underlining the importance of the mechanisms involved in the fundamentals of mitochondrial biology. A hallmark of mitochondrial defects is morphological faults in their distinct membrane architecture. Maintenance of mitochondrial membrane integrity is therefore tightly connected to normal mitochondrial function and to the overall cellular homeostasis. Mitochondrial membrane integrity requires mechanisms that provide constant phospholipid supply to satisfy physiological and stress responses of the organelle. The mechanisms of phospholipid transport between mitochondrial membranes have remained unknown until the identification of the PRELI-TRIAP1 system. PRELI proteins and TRIAP1 assemble in a single unit in mitochondria to regulate phospholipid distribution between mitochondrial membranes. This mechanism appears to be fundamental as it is conserved across all eukaryotes. The ultimate goal of this project was to determine the high resolution 3D structure of the PRELI domain towards the understanding of the molecular mechanisms involved in lipid transport by the PRELI-TRIAP1 system. The work presented here describes structural and biophysical characterisation of human PRELID-TRIAP1 complexes, which, based on structural homology and similarity are important regulators involved in the CL and PE synthetic pathways in mitochondria. Using an MBP expression system, we crystallised and solved the structures of human TRIAP1, and human PRELI domains of PRELID3A and PRELID3B in complex with TRIAP1. Together with mutagenesis, and liposome based functional assays, these atomic details have advanced our understanding of the PRELI-TRIAP1 mechanism, within the wider context of phospholipid metabolism within cells.
Supervisor: Matthews, Steve Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral