RESEARCH: MEMBRANE TRANSPORT
FOLDING PROJECT #15219 PROFILE

This project looks at how changes in the NPC1 protein affect its shape and function. A specific change (I1061T) causes a disease called Niemann-Pick type C1 because it prevents the protein from working properly. The project will study other changes that can fix this problem, helping us understand what parts of the protein are important for its shape and ability to work.

This project aims to reveal the structural interactions that are interrupted in loss-of-structure/loss-of-function mutations for the Niemann-Pick type C1 protein NPC1.

The mutation I1061T has been shown to cause the titular Niemann-Pick type C1 disease by disallowing localization of this lysosomal membrane protein to the lysosome, instead being degraded in the endoplasmic reticulum due to protein misfolding.

Supplementary mutations (on top of the disease-causing mutation) have been shown to recover this activity, and by proxy, the structural stability that allows NPC1 to localize to the lysosomal membrane.

Simulating mutations that recover both structure and function as well as mutations that recover structure only will help reveal the critical interactions necessary for structural stability as well as membrane transporter efficacy.

Niemann-Pick type C1 disease

A rare genetic disorder that affects the body's ability to break down cholesterol.

Niemann-Pick type C1 disease is a rare inherited condition where the body struggles to process cholesterol. This leads to the buildup of cholesterol in certain organs like the brain, liver, and spleen, causing various symptoms such as developmental delays, vision problems, and difficulty swallowing.

NPC1

Niemann-Pick type C1 protein

NPC1 is a protein crucial for transporting cholesterol within cells. Mutations in the gene that codes for NPC1 lead to Niemann-Pick type C1 disease.

Lysosome

A membrane-bound organelle within cells responsible for breaking down waste materials and cellular debris.

Lysosomes are like the recycling centers of our cells. They contain enzymes that break down worn-out cell parts, waste products, and foreign invaders.

Endoplasmic Reticulum

A network of interconnected membranes involved in protein synthesis and lipid metabolism.

The endoplasmic reticulum (ER) is a complex network of tubes and sacs within cells. It plays a vital role in making proteins and lipids (fats) that the cell needs to function.

Protein Misfolding

The incorrect folding of a protein due to genetic mutations or environmental factors.

Protein misfolding happens when proteins don't fold into their correct 3D shapes. This can disrupt their function and lead to various diseases.