RESEARCH: MEMBRANE TRANSPORT
FOLDING PROJECT #15221 PROFILE

This project looks at how changes in the NPC1 protein affect its ability to work properly. A specific change (I1061T) causes disease by making the protein unstable. Researchers are studying other changes that can fix this instability, helping us understand what parts of the protein are important for its structure and function.

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 protein

A lysosomal membrane protein involved in cholesterol transport.

The Niemann-Pick type C1 protein (NPC1) is crucial for transporting cholesterol within cells. It resides in the lysosome, a cellular compartment responsible for breaking down waste materials. Mutations in the NPC1 gene can lead to Niemann-Pick disease type C1, a rare genetic disorder characterized by the accumulation of cholesterol and other lipids in various tissues.

NPC1

Niemann-Pick type C1 protein

NPC1 stands for Niemann-Pick type C1 protein. It's a vital lysosomal membrane protein responsible for transporting cholesterol within cells.

Mutation

A permanent alteration in the DNA sequence.

A mutation is a change in the genetic code, the instructions that make up our DNA. These changes can be small, affecting only one letter of the genetic code, or large, involving entire sections of chromosomes. Mutations can have various effects on an organism, ranging from being harmless to causing disease.

Lysosome

A membrane-bound organelle responsible for degrading waste materials.

Lysosomes are tiny sacs within cells that act as the recycling center. They contain powerful enzymes that break down worn-out cell parts, debris, and engulfed foreign materials. This process is essential for cellular health and function.

Endoplasmic Reticulum

A network of interconnected membranes involved in protein synthesis and transport.

The endoplasmic reticulum (ER) is a complex network of folded membranes within cells. It plays a vital role in protein production, folding, modification, and transportation. There are two types of ER: rough ER, studded with ribosomes for protein synthesis, and smooth ER, involved in lipid synthesis and detoxification.