Sandbox GGC6

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==Fibrinogen==
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=='''Neurotrophin-4'''==
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<StructureSection load='3VEV' size='340' side='right' caption='Caption for this structure' scene=''>
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Fibrinogen ( factor I) is a plasma glycoprotein in the liver, that is important for proper blood clot formication. Fibrinogen is also synthesized in hepatic tissues.
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<StructureSection load='1b98' size='400' side='right' caption='Neurotrophin-4' scene=''>
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Neurotrophin-4 (NT-4) belongs to a group of nerve growth factors that influence nerve cell proliferation through selective and non-covalent interactions with the nerve growth factor receptor. <ref>PMID: 16411893</ref>
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Fibrinogen is composed of three pairs of polypeptide chains: alpha, beta, and gamma <ref>PMID: 28101869</ref>
 
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== Function ==
 
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protease thrombin cleaves fibrinogen into monomers. The formation of monomers, fibrinogen beta, and fibrinogen alpha is insoluble fibrin matrix. fibrin works as a binding or trapping agent in the coagulation process, which creates blood clot.
 
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For small wounds, the polymerized fibrin with platelets forms a hemostatic plug over the wounds site. Fibrin is also anti inflammatory which it protects against IFNG- mediated hemorrhage.
 
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Afibrinogenemic pregnant patients will result in spontaneous miscarriage. Fibrinogen supplemental will allow the patients to sustain the pregnancy, therefore, maternal fibrinogen plays a important role for successful pregnancy.<ref>PMID: 16026273</ref>
 
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== '''Function''' ==
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NT-4 functions as a growth factor in many biological pathways and processes to induce neuronal proliferation. <ref>PMID: 10631974</ref>
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=== Biological Processes ===
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Positive regulation of neurotrophin TRK receptor signaling pathway:
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NT-4 functions as a ligand when binding to neurotrophin receptor tyrosine kinase NTRK2. Auto-phosphorylated NTRK2 dimers that are formed on tyrosine residues in receptor tail as a result of NT-4 binding.
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Adult locomotory behavior <ref>PMID: 10681461</ref>, neuron projection morphogenesis:
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generating projection structures of a neuron, <ref>PMID: 21873635</ref>
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ganglion mother cell fate determination,<ref>PMID: 10681461</ref> epidermis development, <ref>PMID: 9973328</ref> innervation, long term memory, <ref>PMID: 10869436</ref> chemical synaptic transmission modulation and nerve development, <ref>PMID: 21873635</ref> mechanoreceptor differentiation, negative regulation of neuron apoptotic process, and positive regulation of peptidyl-serine phosphorylation, <ref>PMID: 21873635</ref> nerve growth signaling pathway, <ref>PMID:11520933</ref> and sensory organ boundary specification (taste bud development). <ref>PMID: 10479455</ref>
== Disease ==
== Disease ==
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'''Congenital afibrinogenemia (CAFBN)'''
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NT-4, along with other growth factors including neurotrophin-3 (NT-3), brain-derived neurotrophic factor (<scene name='78/781192/Bdnf/1'>BDNF</scene>), and nerve growth factor (NGF) have all shown to be essential for survival of neurons. <ref>PMID: 10631974</ref> <ref>PMID: 16411893</ref> These growth factors have been associated with parts of the cerebrum including the frontal lobe and limbic system because of their involvement in neurological processes like behavior, learning, and memory. <ref>PMID: 16411893</ref> Availability and binding affinity are two factors that contribute to development of Alzheimer's disease and Huntington's disease, as well as neurodegenerative and psychiatric disorders. <ref>PMID: 16411893</ref> Both increased and decreased levels of NT-4 are associated with various disease states that effect mental development and decline. Serum concentration levels of NT-4 and BDNF were found to be higher in patients with autism and in patients with mental retardation <ref>Serum neurotrophin concentrations in autism and mental retardation: a pilot study
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Miyazaki, Kaoru et al.
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This is an inherited blood disorder where the blood does not clot normally. This disease is caused when fibrinogen is totally absent . Changing in position Arg-35 when Thrombin cleaves the site of Fibrinopeptide leads to alpha- Dysfibrinogenemias. <ref>doi: 10.1160/TH14-07-0629</ref>
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Brain and Development, Volume 26, Issue 5, 292 - 295</ref> Defects or mutations in NT-4 has been associated with development of glaucoma.
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Nosebleeds, bleeding from the gums and tongue are commons after a minor trauma for people with this disease. bleedings in the brain and internal organs can occur for affected individuals which can lead to be fatal. However, it's rare. Women with this disease can experience an abnormal heavy menstrual bleeding, they could also have a difficult time carrying a pregnancy, and could result in miscarriages. Newborn with this disease can experience bleeding from the umbilical cord stump after birth. The treatment for this disease includes cryoprecipitate, fibrinogen, and plasma (contains clotting factors). <ref>PMID: 19598064</ref>
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'''Amyloidosis 8 (AMYL8)'''
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This is hereditary disease which insoluble amyloid proteins deposits in body tissues and organs. This tends to abnormal protein build-up and leads to damaged organs and deaths. The disease is caused by a mutation fibrinogen alpha chain.<ref>PMID: 23227278</ref>
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This disease does not show symptoms at first stage. when it gets relatively advanced, the symptoms can be lack of appetite, weight loss, fatigue, weakness, shortness of breath, etc. Due to abnormal protein build-up in body organs, organs can be affected such as heart, liver, kidney, skin, etc. This leads to cardiomyopathy, liver failure, skin rash, nephrotic syndrome. However, nervous system is not affected. There is no treatment for this disease <ref> PMID: 8097946 </ref>.
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'''Congenital Dysfibrinogenemia'''.
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This is either inherited or acquired disorder caused by having abnormal form of fibrinogen. the level of fibrinogen is normal, but the protein doesnt not function properly. This leads to an abnormal blood clot formation; it could be increase or decrease ability to clot. Acquired dysfibrinogenemia is more common and associated with liver disease such as hepatitis, liver tumors.
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Most of people with this disease have no symptoms and do not need a treatment. <ref> PMID: 25320241 </ref>
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== Relevance ==
== Relevance ==
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NT-4 is essential for neuron survival and proliferation throughout ones life span so maintaining proper amounts in the body is needed to stay healthy. Neuron growth factors are currently being used as biomarkers to study the relationship between them and various mental disease states including depression, schizophrenia, autism, Alzheimer's and Huntington's disease. Knowing the cause of variance in these levels is key for prevention of certain neurological disorders.
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Depletion and/or unavailable receptor binding sites are also being studied to further understand these mechanisms.
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== Structural highlights ==
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NT-4 is a homodimer; Its <scene name='78/781192/Protein-ligand/1'>structure</scene> includes 2 Neurotrophin-4 factors bound with a chloride ion. NT-4 is 130 amino acids in length. This chloride ion is a ligand that binds to nerve growth factor receptors.
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<scene name='78/781192/N_to_c_rainbow/1'>N to C sequence</scene>
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{{Template:ColorKey_N52C3Rainbow}}
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[[Image:Blood-coagulation-pathway.png]]
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Copy and paste the following line where you want the scene link to appear (scroll down if needed) and edit the TextToBeDisplayed:
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This process called coagulation cascade (or secondary hemostasis) forming a stable insoluble fibrin clot. The process has two pathways which are intrinsic and extrinsic pathway. These pathways eventually join to become the common pathway.
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<scene name='78/781192/Temperature/1'>Temperature Value</scene>
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{{Template:ColorKey_TemperatureRelative}}
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''- Intrinsic pathway:'' This begins with activated factor XII, which then activates factor XI. Activated factor XI further activates factor IX, which activates factor VIII to form tenase complex on a phospholipid surface to activate factor X in the common pathway.
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[[Image:1b98 entity 1 front image-800x800.png]]
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''- Extrinsic pathway:'' when a tissue is damaged, it releases tissue factor to activate factor VII, which then activates factor X.
 
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''
 
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''- Common pathway:'''' either intrinsic pathway or extrinsic pathway activates factor X causes formation of thrombin from prothrombin. Thrombin will cleave fibrinogen to insoluble fibrin and also activate factor XIII. Factor XIII and fibrin bind together forming a stable bond and attach to platelets. <ref>PMID: 25535411</ref>
 
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</StructureSection>
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== '''Structural highlights''' ==
 
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This is the <scene name='78/781192/3ghg/3'>structure of fibrinogen</scene>. It is composed of one pairs of alpha, beta, and gamma polypeptides. the polypeptides are oriented to <scene name='78/781192/N-c_terms/3'>N-terms</scene>ends meet to form a central E domain which is showed in blue. Both domain on the side of E domain called D domain. The N terms ends of polypeptides are cleaved by thrombin to form gel forming fibrin from soluble fibrin <ref>PMID: 28101869 </ref>.
 
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The back line is <scene name='78/781192/Asp_364/1'>Asp 364</scene>, which is an important residue. The mutation of this residue can cause Congenital Dysfibrinogenemia. <ref>doi.org/10.1054</ref>
 
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This is a <scene name='78/781192/Hydrophobic_and_polar/3'>hydrophilic and hydrophobic</scene> structure. <ref>doi.org/10.1007/BF01024625(/ref>
 
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</StructureSection>
 
== References ==
== References ==
<references/>
<references/>

Current revision

Neurotrophin-4

Neurotrophin-4

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References

  1. ↑ Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006 Feb;110(2):167-73. doi: 10.1042/CS20050163. PMID:16411893 doi:http://dx.doi.org/10.1042/CS20050163
  2. ↑ Robinson RC, Radziejewski C, Spraggon G, Greenwald J, Kostura MR, Burtnick LD, Stuart DI, Choe S, Jones EY. The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci. 1999 Dec;8(12):2589-97. PMID:10631974
  3. ↑ Liebl DJ, Klesse LJ, Tessarollo L, Wohlman T, Parada LF. Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice. Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2297-302. doi:, 10.1073/pnas.040562597. PMID:10681461 doi:http://dx.doi.org/10.1073/pnas.040562597
  4. ↑ Gaudet P, Livstone MS, Lewis SE, Thomas PD. Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Brief Bioinform. 2011 Sep;12(5):449-62. doi: 10.1093/bib/bbr042. Epub 2011 Aug, 27. PMID:21873635 doi:http://dx.doi.org/10.1093/bib/bbr042
  5. ↑ Liebl DJ, Klesse LJ, Tessarollo L, Wohlman T, Parada LF. Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice. Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2297-302. doi:, 10.1073/pnas.040562597. PMID:10681461 doi:http://dx.doi.org/10.1073/pnas.040562597
  6. ↑ Botchkarev VA, Botchkareva NV, Welker P, Metz M, Lewin GR, Subramaniam A, Bulfone-Paus S, Hagen E, Braun A, Lommatzsch M, Renz H, Paus AR. A new role for neurotrophins: involvement of brain-derived neurotrophic factor and neurotrophin-4 in hair cycle control. FASEB J. 1999 Feb;13(2):395-410. doi: 10.1096/fasebj.13.2.395. PMID:9973328 doi:http://dx.doi.org/10.1096/fasebj.13.2.395
  7. ↑ Xie CW, Sayah D, Chen QS, Wei WZ, Smith D, Liu X. Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4 gene. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8116-21. doi: 10.1073/pnas.140204597. PMID:10869436 doi:http://dx.doi.org/10.1073/pnas.140204597
  8. ↑ Gaudet P, Livstone MS, Lewis SE, Thomas PD. Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Brief Bioinform. 2011 Sep;12(5):449-62. doi: 10.1093/bib/bbr042. Epub 2011 Aug, 27. PMID:21873635 doi:http://dx.doi.org/10.1093/bib/bbr042
  9. ↑ Gaudet P, Livstone MS, Lewis SE, Thomas PD. Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Brief Bioinform. 2011 Sep;12(5):449-62. doi: 10.1093/bib/bbr042. Epub 2011 Aug, 27. PMID:21873635 doi:http://dx.doi.org/10.1093/bib/bbr042
  10. ↑ Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci. 2001;24:1217-81. doi: 10.1146/annurev.neuro.24.1.1217. PMID:11520933 doi:http://dx.doi.org/10.1146/annurev.neuro.24.1.1217
  11. ↑ Liebl DJ, Mbiene JP, Parada LF. NT4/5 mutant mice have deficiency in gustatory papillae and taste bud formation. Dev Biol. 1999 Sep 15;213(2):378-89. doi: 10.1006/dbio.1999.9385. PMID:10479455 doi:http://dx.doi.org/10.1006/dbio.1999.9385
  12. ↑ Robinson RC, Radziejewski C, Spraggon G, Greenwald J, Kostura MR, Burtnick LD, Stuart DI, Choe S, Jones EY. The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci. 1999 Dec;8(12):2589-97. PMID:10631974
  13. ↑ Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006 Feb;110(2):167-73. doi: 10.1042/CS20050163. PMID:16411893 doi:http://dx.doi.org/10.1042/CS20050163
  14. ↑ Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006 Feb;110(2):167-73. doi: 10.1042/CS20050163. PMID:16411893 doi:http://dx.doi.org/10.1042/CS20050163
  15. ↑ Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006 Feb;110(2):167-73. doi: 10.1042/CS20050163. PMID:16411893 doi:http://dx.doi.org/10.1042/CS20050163
  16. ↑ Serum neurotrophin concentrations in autism and mental retardation: a pilot study Miyazaki, Kaoru et al. Brain and Development, Volume 26, Issue 5, 292 - 295
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