Neurofibromin: Difference between revisions

Glutamine 61 of Ras is a residue that facilitates the conversion of GTP to GDP, turning Ras from its active state to inactive state. There is a catalytic water molecule that glutamine interacts with to position the molecule for a nucleophilic attack on the gamma phosphate of GTP. Mutations of this residue have been related to lower rates of hydrolysis. <ref name= ''Frech''>PMID:8136358</ref>. Tyrosine 32 makes water-mediated hydrogen bonds with the gamma phosphate of GTP. This position is also where Ras is phosphorylation to promote the activity of GTPase-activating proteins and GTP hydrolysis. <ref name= ''Bunda''>DOI:10.1038/ncomms9859</ref>  

== Disease Relevance ==

Mutations to the neurofibromin protein are implicated in the progression of Neurofibromatosis type 1. Neurofibromatosis type 1 is a condition where cancer develops by inactivating the Ras suppression effects of NF, allowing Ras to behave as an oncogene. Neurofibromatosis type 1 is an autosomal dominant disorder that affects 1 in 3,000 people. The ''NF'' gene has the highest mutation rate of any human gene, adding to the prevalence of cancers related to neurofibromin mutations<ref name= ''Lupton''>PMID:34887559</ref>. Furthermore, these mutations consist heavily of ''de novo'' mutations<ref name= ''Abramowicz''>PMID:25182393</ref>. NF1 primarily causes tumors in the central and peripheral nervous systems, but often has a multisystem expression including tumors in the dermatologic, cardiovascular, gastrointestinal, and orthopedic systems<ref name= ''Cimino''>PMID:29478615</ref>. The wide range of presentations is consistent with the multiplicity of mutations observed in the causative protein<ref name= ''Ly''>PMID:31582003</ref>. This multiplicity derives from the immense size and homo dimeric nature of the neurofibromin protein that allows for otherwise innocuous mutations to wreak havoc on the conformations of the protein as well as its ability to bind to the Ras protein as positioning of NF is highly important.

[[Image:Signal_transduction_pathways.png|600 px|right|thumb|Figure 2: Downstream proliferation of Ras signals have a variety of impacts, including gene regulation, cell proliferation, and cell growth; By cybertory - This file was derived from: Signal transduction v1.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12081090]]

Misregulated [http://https://proteopedia.org/wiki/index.php/GTPase_HRas Ras activity] can lead to uncontrolled signaling in many different cell signaling pathways. Figure 2 provides an overview of the pathways that are connected to Ras, such as the MEK pathway.