RESEARCH: CANCER
FOLDING PROJECT #16580 PROFILE

This project looks at how changes in a protein called PP2A can cause intellectual disability and cancer. PP2A usually keeps itself inactive, but mutations can make it more active. Researchers are using computer simulations and experiments to understand how these mutations work and how they affect PP2A's shape.

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

Protein phosphatase 2A (PP2A) mutations have been linked to intellectual disability and cancer, potentially disrupting the protein’s autoinhibition mechanism and phosphorylation-induced activation.

The mutations are located distant from the active and substrate sites, their impact on the mechanism remains unclear.

Allosteric pathway analysis, integrated with biochemical experiments, probes PP2A autoinhibition.

In the wild-type (WT) system, regulatory subunit B56δ's C-arm impedes active and substrate sites, enacting dual autoinhibition.

The disease mutant, E198K, markedly weakens the WT's allosteric pathways by taking a different route, favoring substrate site exposure.

A novel path clustering algorithm, introduced in this work, streamlines the allosteric pathway analysis.

E198K and phosphorylated WT share strikingly similar allosteric channels, suggesting a conserved autoinhibition alleviation between these variants.

Folding at home will be used to study the conformational change involved in the opening of this N/C-arm interface in order to determine why the E198K mutant is more active than the WT.

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Protein phosphatase 2A

An enzyme that removes phosphate groups from proteins.

Protein phosphatase 2A (PP2A) is a crucial enzyme that regulates cellular processes by removing phosphate groups from proteins. This dephosphorylation activity plays a vital role in cell signaling, growth, and development. Dysregulation of PP2A has been linked to various diseases, including cancer and intellectual disability.

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Mutations

Permanent changes in the DNA sequence.

Mutations are alterations in the genetic code (DNA) that can affect protein production and function. These changes can be inherited or acquired through environmental factors. Mutations play a role in evolution, disease development, and individual traits.

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Intellectual Disability

A neurodevelopmental disorder characterized by limitations in intellectual functioning and adaptive behavior.

Intellectual disability is a condition that affects cognitive abilities such as learning, problem-solving, and communication. Individuals with intellectual disability may also have difficulties with daily living skills and social interactions. Causes include genetic disorders, prenatal conditions, or environmental factors.

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Cancer

A group of diseases characterized by uncontrolled cell growth.

Cancer is a disease that occurs when cells grow and divide uncontrollably. This abnormal growth can invade surrounding tissues and spread to other parts of the body (metastasis). There are many types of cancer, each with unique characteristics and treatments.

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Autoinhibition

A regulatory mechanism where a protein or enzyme inhibits its own activity.

Autoinhibition is a self-regulating process in which a molecule, often an enzyme, prevents its own function. This mechanism helps control cellular processes by preventing excessive or unwanted activity.

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Phosphorylation

The addition of a phosphate group to a molecule.

Phosphorylation is a vital process in cellular signaling where a phosphate group is added to a molecule, typically a protein. This modification can alter the molecule's activity, interactions, and overall function.

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Allosteric Pathway

A regulatory pathway that involves binding of a molecule to a site other than the active site.

Allosteric pathways are complex regulatory networks where molecules bind to sites distinct from the active site, influencing the enzyme's activity. This modulation plays a crucial role in controlling cellular processes and signaling.

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Wild-Type

A normal or typical form of a gene or organism.

Wild-type refers to the standard or most common form of a gene or organism. It contrasts with mutant forms that have alterations in their DNA sequence.

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Disease Mutant

A variant of a gene or protein that is associated with disease.

Disease mutants are altered versions of genes or proteins that contribute to the development or progression of diseases. These mutations can disrupt normal cellular functions.