Sandbox Reserved 1710: Difference between revisions

[[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]

Neurofibromin is encoded by [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], located on chromosome 17. Neurofibromin functions as a tumor suppressor through its association with the protein [https://proteopedia.org/wiki/index.php/Ras Ras]. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin are associated with diseases such as [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas]. (FLESH OUT INTRODUCTION)

== Function ==

Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase]. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. (DEFINE RAS) Neurofibromin is brought to the membrane to associate with Ras by [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. (DEFINE SPRED1) Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division are inhibited. (MECHANISTIC EXPLANATION).

[[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]

== Structure ==

Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the open conformation.