RESEARCH: CANCER
FOLDING PROJECT #18452 PROFILE

This project studies how changes in protein shape affect their function. They're using computer simulations to understand how mutations impact folding, starting with small proteins and moving on to MeCP2, a protein linked to Rett syndrome. Accurate protein folding models could lead to better treatments for diseases like Rett syndrome.

Note: This TLDR is a simplication and may not be 100% accurate.

The function of a protein depends on its native shape, or fold.

Deciphering the sequence-dependent process by which proteins reach their folded state has been the goal of much experimental and computational work, and the inspiration for the e Folding@home project.

Small “fast folding” mini-proteins, such as the protein G B1 domain (GB1) and hpin1 WW domain, have been studied extensively both experimentally and through simulation, producing a wealth of data on wild-type protein function, and much insight on how mutations affect the folding reaction.

In 2022, the Voelz lab published a study on the folding reaction of a transcription factor, FOXO1, in which a simple hydrophobic transfer model was used to accurately predict mutational effects from models derived from massively parallel Folding@home simulations (Novack et al.).

We found that this model made more accurate predictions than other state of the art methods of mutational analysis.

We hypothesize that this is because our simulations have more accurate descriptions of the unfolded ensemble of a protein than other methods, highlighting the importance of adequately describing the unfolded state of a protein in determining mutational effects on folding reaction.

In these projects, we aim to validate this hypothesis on the well studied miniproteins GB1 and hpin1 WW domain, as well as the MeCP2 protein.

MeCP2 is a protein that binds methylated DNA and is found in high levels in nerve cells.

the main disease associated with mutations of MeCP2 is Rett syndrome, a neurological disorder that severely impairs people’s ability to speak, walk, eat, and breathe.

The gene lives on X chromosomes, thus for people with an XY chromosomal configuration (lacking a complimentary natively functioning gene), this disease can be fatal within the first 2 years due to encephalopathy.

There are at least 4668 mutational variants of MeCP2 identified, with 1171 being in the only structured region of the protein, the MBD.

Stability effects of mutation in MeCP2 have been investigated both experimentally and computationally, which makes it a promising test case for both validation of hydrophobic transfer as a model of mutation effects, as well as an opportunity to gain atomic insight that can elucidate new avenues for therapeutics targeting MeCP2.

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protein

Large biomolecule essential for life processes.

Proteins are complex molecules that perform many vital functions in living organisms. They are made up of chains of amino acids and fold into specific shapes that determine their function. Proteins are involved in a wide range of processes, including catalyzing reactions, transporting molecules, providing structural support, and regulating cellular processes.

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fold

The three-dimensional shape of a protein.

The 'fold' refers to the unique three-dimensional shape that a protein takes on. This shape is crucial for the protein's function because it determines how it interacts with other molecules. The process by which a protein folds into its correct shape is called protein folding.

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mutation

A change in the DNA sequence.

A mutation is a permanent alteration in the DNA sequence of an organism. Mutations can be caused by factors such as errors during DNA replication, exposure to radiation, or certain chemicals. Some mutations have no effect on the organism, while others can lead to changes in protein structure and function.

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transcription factor

A protein that binds to DNA and regulates gene expression.

Transcription factors are proteins that play a crucial role in controlling which genes are turned on or off. They bind to specific regions of DNA called promoters and enhancers, influencing the rate of transcription (the process of making RNA from DNA). This regulation is essential for cellular differentiation, development, and response to environmental signals.

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MeCP2

Methyl CpG binding protein 2

MeCP2 is a protein that binds to methylated DNA. It plays a role in gene regulation and is particularly important for brain development and function. Mutations in the MeCP2 gene can lead to Rett syndrome, a neurodevelopmental disorder characterized by intellectual disability, autism spectrum disorder, and other neurological symptoms.

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Rett syndrome

A rare neurodevelopmental disorder.

Rett syndrome is a rare genetic disorder that primarily affects females. It is characterized by a period of normal development followed by regression in skills such as language, motor function, and social interaction. Other symptoms include seizures, breathing irregularities, and scoliosis. Rett syndrome is caused by mutations in the MeCP2 gene.

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MBD

Methyl-binding domain

The MBD is a protein domain that specifically binds to methylated DNA. It plays a role in regulating gene expression and is found in various proteins involved in chromatin remodeling and transcriptional repression.