Diseases that result from failures in the breakdown of old molecules

Problem Title

Diseases that result from failures in the breakdown of old molecules

Scientific Title

Structural study of an alternative lysosomal transport receptor

Shaul Kushinksy
Biochemistry and Molecular Biology
iCons Concentration: 
iCons Class Year: 
Class of 2014
Executive Summary 

The lysosome is a cellular organelle containing dozens of enzymes responsible for the catabolism of macromolecules, and is involved in over 50 different genetic and metabolic diseases. Lysosomal enzymes fold within the endoplasmic reticulum, and are trafficked through the golgi apparatus to the lysosome via a transport receptor. One such receptor, lysosomal integral membrane protein type 2 (LIMP-2), was recently identified to specifically transport the lysosomal hydrolase β-glucocerebrosidase, but has also been shown to transport enterovirus 71.

An absence of LIMP-2 activity, usually due to mutations in SCARB2, the gene encoding for LIMP-2, causes the disease action myoclonus-associated renal failure syndrome. The level of LIMP-2 function is also linked to the severity of the most common lysosomal storage disease, Gaucher disease. Therefore, understanding the binding between LIMP-2 and β-glucocerebrosidase is crucial to determining the role of LIMP-2 in lysosomal diseases.

Using X-ray crystallography, we are determining structures of LIMP-2 in different environmental conditions. We present structures from several native crystals, and a crystal infused with ethyl mercury phosphate. By altering the crystal environment, we will observe which parts of the receptor change, and how the changes might impact dimer formation or cargo binding. Understanding the LIMP-2 structure and β-glucocerebrosidase binding mechanism will allow for the creation of powerful therapeutics to treat the lysosomal diseases action myoclonus-associated renal failure syndrome and Gaucher disease.

Problem Keywords: 
Gaucher Disease
Scientific Keywords: 
X-ray crystallography