Sandbox Reserved 1721

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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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You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

1 Function
2 Disease
3 Relevance
4 Structure

Function

Disease

Relevance

Structure

Neurofibromin is a large protein of 2818 amino acids ^[3] and is a homodimer that exists in two conformations.

Domains

Neurofibromin consists of multiple domains: N-HEAT/ARM, GRD, Sec14-PH, GAPEx, and C-HEAT/ARM. The two most characterized domains of neurofibromin are the Sec14-PH and GRD domains. Each of the protomers of neurofibromin contains these domains.

The N-HEAT/ARM and C-HEAT/ARM are rigid, which makes them critical in the rearrangement of the Gap-related and Sec14-PH domains. In the closed conformation, the HEAT/ARM domains cover the GRD, preventing the binding of Ras through steric hinderance. The HEAT/ARM cores are made up of many alpha helices. ^[4]

conformations

closed

The closed state of neurofibromin has both protomers in a closed conformation, which inhibits the binding of Ras to the GRD of neurofibromin due to the HEAT/ARM blocking the GRD. A metal binding site between the N-HEAT/ARM domain and the GRD-Sec14-PH linker stabilize the closed conformation. This site is coordinated by three residues, C1032, H1558, and H1576, and a water molecule. This binding site is preferential for zinc.

open

The open state of neurofibromin has one protomer in a open conformation and the other in a closed conformation. The protomer in the open conformation allows for the binding of Ras because of reorientation of the GRD and Sec14-PH domains. In the open conformation, the metal binding site found in the closed conformation is lost due to separation of the N-HEAT/ARM and the cysteine residue from the histidine residues founds in the GRD-Sec14-PH linker.

transition between open and closed conformation

rearrangement of connective loops between domains triad of residues from nf GAPex

Spred1

CSRD and CTD

The Cysteine-Serine-rich domain (CSRD) and C-terminal domain (CTD) contain phosphorylation sites. The CSRD is able to be phosphorylated by protein kinases A and C Phosphorylation by protein kinase C is a positive regulator of neurofibromin activity. The CTD is phosphorylated primarily by protein kinase C. This domain is a negative regulator of neurofibromin activity if particular residues are phosphorylated. CTD contains a nuclear localization signal as well.

scenes

References

↑ 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
↑ 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
↑ Bergoug M, Doudeau M, Godin F, Mosrin C, Vallee B, Benedetti H. Neurofibromin Structure, Functions and Regulation. Cells. 2020 Oct 27;9(11). pii: cells9112365. doi: 10.3390/cells9112365. PMID:33121128 doi:http://dx.doi.org/10.3390/cells9112365
↑ 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

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 GAPex
 ===Spred1===
+==== CSRD and CTD ====
+The Cysteine-Serine-rich domain (CSRD) and C-terminal domain (CTD) contain phosphorylation sites. The CSRD is able to be phosphorylated by protein kinases [https://en.wikipedia.org/wiki/Protein_kinase_A A] and [https://en.wikipedia.org/wiki/Protein_kinase_C C] Phosphorylation by protein kinase C is a positive regulator of neurofibromin activity. The CTD is phosphorylated primarily by protein kinase C. This domain is a negative regulator of neurofibromin activity if particular residues are phosphorylated. CTD contains a nuclear localization signal as well.
 </StructureSection>