Cell biology and biochemistry of protein transport towards lysosome-related organelles

• Applicant: Dr. Christina Schindler
• Subject Area: Cell Biology
• Term: from 2008 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 90662341

The early endosome is a an important sorting station for cargo proteins that recycle to the plasma membrane or the trans-Golgi-network, as well as for proteins destined to the lysosome. Transmembrane cargo proteins or sorting receptors that bind luminal cargo have sorting signals within their cytosolic domains. Maintenance of cellular homeostasis thus requires a system that recognizes these determinants on cargo proteins and directs them to budding vesicles destined for a specific target organelle. Defects in transport of cargo to lysosomes leads to aberrant lysosome function and results in lysosomal storage diseases. In addition to normal lysosomes, which function in the degradation of a broad range of substrates, certain cell types contain specialized lysosomes, termed lysosome-related organelles (LROs), that fulfill biosynthetic and storage functions. A prominent example for LROs are melanosomes in melanocytes that synthesize and store the pigment, melanin. We are particularly interested in a group of protein complexes termed biogenesis of lysosome-related organelle complexes (BLOC) that are involved in protein trafficking to LROs. Hermansky-Pudlak Syndrome (HPS) is a group of disorders in which defects in BLOC complexes cause albinism, prolonged bleeding, pulmonary fibrosis and ulcerative colitis. There are three BLOCs named BLOC-1, BLOC-2 and BLOC-3. The BLOC-1 complex is required to transport critical components of LROs at an early stage of their biogenesis, yet its precise role in the process has not been resolved. We aim to use cell biological, biochemical and structural methods to understand BLOC-1 function at the molecular level. A major goal is to identify regulators and effectors of the BLOC-1 complex in order to integrate BLOC-1 function into a cellular machinery responsible for melanosome biogenesis.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Juan S. Bonifacino