Sandbox Reserved 1710
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Neurofibromin functions as a tumor suppressor protein. Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as SPRED1. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an arginine finger (R1276) present in the GRD of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains of Neurofibromin are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the Ras signaling pathway by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.[[Image:mechanismofRas.png|400 px|lef|thumb|Figure Legend]] | Neurofibromin functions as a tumor suppressor protein. Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as SPRED1. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an arginine finger (R1276) present in the GRD of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains of Neurofibromin are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the Ras signaling pathway by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.[[Image:mechanismofRas.png|400 px|lef|thumb|Figure Legend]] | ||
== Disease == | == Disease == | ||
| - | Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its guanine triphosphatase-activating protein (GAP) activity, therefore when there are mutations to the NF1 gene that prevents the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system. | + | Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its guanine triphosphatase-activating protein (GAP) activity, therefore when there are mutations to the NF1 gene that prevents the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system. |
== Student Contributors == | == Student Contributors == | ||
*Hannah Luchinski | *Hannah Luchinski | ||
Revision as of 18:32, 28 March 2022
| This Sandbox is Reserved from February 28 through September 1, 2022 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1700 through Sandbox Reserved 1729. |
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Human Neurofibromin - The Tumor Suppressor Gene
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References
- ↑ Naschberger A, Baradaran R, Rupp B, Carroni M. The structure of neurofibromin isoform 2 reveals different functional states. Nature. 2021 Nov;599(7884):315-319. doi: 10.1038/s41586-021-04024-x. Epub 2021, Oct 27. PMID:34707296 doi:http://dx.doi.org/10.1038/s41586-021-04024-x
- ↑ Lupton CJ, Bayly-Jones C, D'Andrea L, Huang C, Schittenhelm RB, Venugopal H, Whisstock JC, Halls ML, Ellisdon AM. The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1. Nat Struct Mol Biol. 2021 Dec;28(12):982-988. doi: 10.1038/s41594-021-00687-2., Epub 2021 Dec 9. PMID:34887559 doi:http://dx.doi.org/10.1038/s41594-021-00687-2
