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Protein Phosphatase 2A

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Structure and Function

2NYL

2NPP

2NYM

HEAT Repeat Motif

PP2A belongs in the HEAT Repeat Motif or Huntington-elongation-A subunit-TOR. The main backbone of PP2A are 15 repeating units or HEAT units, each composed of a conserved 39-residue sequence.The HEAT Motif has a signature sequence of conserved residues asparagine at position 19 and arginine at position 25. Each HEAT unit consists of a pair of antiparallel alpha-helices. These antiparallel helices assemble in a L-shaped fashion resulting in an overall shape of a double layer of alpha helices. These HEAT units are responsible for a majority of the overall protein packing and structure by interactions of the ridges of each HEAT unit.

Huntington's Disease

One unique feature of the Huntington's Disease protein, Htt, is that it features a HEAT repeat like that of PP2A. Continued understanding of how PP2A heat repeat operates could provide valuable insight in understanding the mechanisms of Huntington's Disease function. Huntington's Disease is a genetically inherited disease that is dominant in nature which means an infected parent will have a 50% chance of transmission to their child. It is classified as a neurodegenerative disorder that will result in death. The disease can strike as early as childhood but usually starts to affect the individual from the ages of 35 to 45 years of age. Initial signs consists of mood changes for the first few years followed by disruption of motor skills called chorea. Chorea is a term to describe jerky uncontrolled movements of the extremities followed by the entire body as the disease progresses. Chorea like conditions are also present in individuals with Parkinson's Disease which is a little more publically known. Huntington's Disease continues to affect the mind as well as the body. The later stages of the disease will result in a individual that could be described as being as a schizophrenic with dementia and Alzheimer's that also has Parkinson's Disease. The individual will fade both mentally and physically until death comes in the common form of heart failure or pneumonia from the weakened condition. This disease creates a lot of controversy in the genetic counseling community due to the fact that it can now be detected as early as in-vitro fertilization. The ramifications from a positive diagnosis would be considered by most as a life shattering event. There is a quote from Campbell a biology book that poses the question of 'At what point would it be beneficial to know that the individual has a incurable fatal disease that will generally result in death in the early fifties?' The answer to the question becomes apparent when one considers family planning. Recent advancements in in-vitro technology allow scientists to fertilize multiple eggs and select embryos free from Huntington's Disease without informing the donor of the egg or sperm if they are a carrier of the disease. Understanding how HEAT repeat mechanisms work in proteins like PP2A and how to disrupt their function could yield valuable insight in battling Huntington's Disease.

Structural highlights

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References

1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644