Neurofibromin: Difference between revisions
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The Gap-related domain, or GRD, is the catalytic domain of neurofibromin. This domain also contains a tubulin-binding domain. Its main catalytic mechanism is the hydrolysis of GTP-bound Ras into GDP-bound Ras, which converts Ras from its active form into its inactive form. The GRD provides an arginine residue, known as the arginine finger, to Ras. | The Gap-related domain, or GRD, is the catalytic domain of neurofibromin. This domain also contains a tubulin-binding domain. Its main catalytic mechanism is the hydrolysis of GTP-bound Ras into GDP-bound Ras, which converts Ras from its active form into its inactive form. The GRD provides an arginine residue, known as the arginine finger, to Ras. | ||
==== SEC-PH ==== | ==== SEC-PH ==== | ||
The Sec-PH domain is the lipid-binding domain of neurofibromin. In the closed conformation of neurofibromin, the hydrophobic core is blocked by the Gap-related domain. The open conformation allows the hydrophobic core in the Sec cavity to be accessible and exposed. | The Sec-PH domain is the lipid-binding domain of neurofibromin. In the <scene name='90/904326/Sec14ph_and_grd_closed/2'>closed conformation</scene> of neurofibromin, the hydrophobic core is blocked by the Gap-related domain. The <scene name='90/904326/Sec15ph_and_grd_open/2'>open conformation</scene> allows the hydrophobic core in the Sec cavity to be accessible and exposed. | ||
==== CSRD and CTD ==== | ==== 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. It also plays an important role in tubulin binding, as it helps in the transition from metaphase to anaphase. CTD contains a nuclear localization signal as well. | 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. It also plays an important role in tubulin binding, as it helps in the transition from metaphase to anaphase. CTD contains a nuclear localization signal as well. | ||
===Important Structural Features=== | ===Important Structural Features=== | ||
====Active Site==== | ====Active Site==== | ||
The active site for GTP hydrolysis of Ras is located in the Gap-related domain of neurofibromin. The catalytic residues include R68, Q61, and Y32, as well as magnesium and water molecules. Arginine is referred to as an “arginine finger” because it points into the binding site of GTP to stabilize and orient the position of glutamine through a network of hydrogen bonds between water molecules. This arginine comes from the Gap-related domain of neurofibromin. When GDP is bound, glutamine is too far away to perform its catalytic action. Glutamine interacts with the gamma phosphate via a hydrogen bond created from an interaction between a water molecule and the gamma phosphate. When GTP is bound, tyrosine moves inward to face it. In the GDP bound form, tyrosine faces outward. | The <scene name='90/904326/Active_site_with_residues/6'>active site</scene> for GTP hydrolysis of Ras is located in the Gap-related domain of neurofibromin. The catalytic residues include R68, Q61, and Y32, as well as magnesium and water molecules. Arginine is referred to as an “arginine finger” because it points into the binding site of GTP to stabilize and orient the position of glutamine through a network of hydrogen bonds between water molecules. This arginine comes from the Gap-related domain of neurofibromin. When GDP is bound, glutamine is too far away to perform its catalytic action. Glutamine interacts with the gamma phosphate via a hydrogen bond created from an interaction between a water molecule and the gamma phosphate. When GTP is bound, tyrosine moves inward to face it. In the GDP bound form, tyrosine faces outward. | ||
====Arginine Finger==== | ====Arginine Finger==== | ||
<scene name='90/904325/Arginine_finger_and_gdp/2'>The catalytic glutamine is too far away from the GDP substrate for any interaction to occur.</scene> | <scene name='90/904325/Arginine_finger_and_gdp/2'>The catalytic glutamine is too far away from the GDP substrate for any interaction to occur.</scene> | ||
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===Downstream Effects=== | ===Downstream Effects=== | ||
[[Image:Signal_transduction_pathways.png|400 px|right|thumb|Figure 2; 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]] | [[Image:Signal_transduction_pathways.png|400 px|right|thumb|Figure 2; 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]] | ||
The NF1 gene that neurofibromin encodes has a high mutation rate, however it is difficult to detect the mutations because of how large the protein is and how randomly the mutations are distributed across the protein. Many of the mutations have been detected in the catalytic Gap-related domain. Misregulated 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. Eventually, the pathways relate to gene regulation and cell proliferation. If Ras is hyperactive, cell overgrowth and cancer can result. A focus of drug design is the suppression of Ras and its downstream signaling pathways. | The NF1 gene that neurofibromin encodes has a high mutation rate, however it is difficult to detect the mutations because of how large the protein is and how randomly the mutations are distributed across the protein. Many of the mutations have been detected in the catalytic Gap-related domain. 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. Eventually, the pathways relate to gene regulation and cell proliferation. If Ras is hyperactive, cell overgrowth and cancer can result. A focus of drug design is the suppression of Ras and its downstream signaling pathways. | ||
== Disease Relevance == | == Disease Relevance == | ||
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</StructureSection> | </StructureSection> | ||
