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Structural basis of selective autophagy mediated by cargo receptors

Objective

Autophagy is a bulk cellular degradation pathway in which double-membrane vesicles engulfe large and long-lived cytoplasmic structures and target them to lysosomal compartments. Employing an integrated structural biology approach using single-particle cryo-EM and X-ray crystallography, this proposal aims to elucidate the structural details by which the autophagosomal recognition machinery identifies and assembles its cargo for targeting to autophagosomes. It has recently become apparent that selective autophagy requires specific receptors that recognize and recruit defined cargo into molecular assemblies and target them for autophagosomal degradation. Dysfunction of this process is implicated in a number of important human pathologies, such as cancer, neurodegeneration and myopathies. A precise understanding of the molecular mechanisms underlying selective autophagy requires the structural characterization of the molecular complexes involved in this process. First, the ultrastructural architecture of homo-oligomeric receptor assemblies will be established. Second, the structural organization of cargo-receptor complexes will be defined for a hetero-oligomeric, mechanosensitive model complex involved in muscle homeostasis using a combination of cryo-EM and X-ray crystallography. Third, oligomeric changes of cargo-receptor assemblies will be related to cellular function. In its aim to establish a multi-resolution view on the molecular principles of selective autophagy, this proposal has the potential to fundamentally advance our current understanding of this important degradation pathway.

Field of science

  • /natural sciences/biological sciences/molecular biology/structural biology
  • /natural sciences/earth and related environmental sciences/geology/mineralogy/crystallography

Call for proposal

FP7-PEOPLE-2012-IEF
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Address
Meyerhofstrasse 1
69117 Heidelberg
Germany
Activity type
Research Organisations
EU contribution
€ 161 968,80
Administrative Contact
Jillian Rowe (Ms.)