RESEARCH: MEMBRANE TRANSPORT
FOLDING PROJECT #15222 PROFILE

This project studies how changes in the NPC1 protein affect its ability to work properly inside cells. Some mutations cause the protein to misfold and break down, leading to a disease called Niemann-Pick type C1. The project aims to find out which parts of the protein are important for its shape and function by studying mutations that can fix these problems.

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

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

Niemann-Pick type C1 disease is a rare inherited disorder caused by mutations in the NPC1 gene. This gene provides instructions for making a protein called NPC1, which plays a crucial role in transporting cholesterol and other lipids within cells. Due to the faulty NPC1 protein, fats build up in various organs, leading to problems such as neurological issues, enlarged liver and spleen, and vision difficulties.

NPC1

Niemann-Pick C1 Protein

NPC1 is a protein vital for transporting cholesterol and other fats within cells. It resides in the lysosomes, cellular compartments responsible for breaking down waste materials. Mutations in the NPC1 gene disrupt this protein's function, leading to Niemann-Pick type C1 disease.

Mutation

A permanent alteration in the DNA sequence that makes up a gene.

Mutations are changes in the genetic code that can alter the function of genes. They can be inherited from parents or arise spontaneously. Mutations can have various effects, ranging from harmless to causing diseases like Niemann-Pick type C1.

Lysosome

A membrane-bound organelle found in eukaryotic cells that contains enzymes for breaking down waste materials and cellular debris.

Lysosomes are tiny compartments within cells responsible for recycling and disposing of waste. They contain powerful enzymes that break down various substances, including worn-out cell parts, engulfed bacteria, and excess cellular components.

Endoplasmic reticulum

A network of interconnected membranes within eukaryotic cells that plays a role in protein synthesis and lipid metabolism.

The endoplasmic reticulum (ER) is a complex network of folded membranes extending throughout the cell. It's involved in producing proteins, folding them into their correct shapes, and transporting lipids. The ER has two main types: rough ER, which has ribosomes attached for protein synthesis, and smooth ER, which lacks ribosomes and is involved in lipid metabolism.