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| '''Histone H3.3'''<StructureSection load='3WTP' size='340' side='right' caption='Caption for this structure' scene=''>
| | ==Kinesin Motor Domain== |
| == Introduction ==
| | <StructureSection load='1bg2' size='340' side='right' caption='Kinesin Protein' scene=''> |
| Histone H3.3 is a variant histone of H3 which has the gene name H3.3A and this particular protein is found in Humans. The location of this can be found in the nucleus and in the chromosome.<ref>https://www.uniprot.org/uniprot/P84243</ref>
| | Kinesin is an ATP-dependent motor protein responsible for the transportation of cargo. It is a heterotetramer composed of light and heavy chains. |
| == Function ==
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| [https://www.uniprot.org/uniprot/P84243 Histone H3] replaces H3 in a range of nucleosomes in active genes and it takes over the original H3 in non dividing cells. Nucleosomes wrap around and compact DNA into chromatin which limits DNA access to cellular machineries which need DNA as a template. Histones play an important role in regulation of transcription, DNA repair, DNA replication and also chromosomal stability. Access to DNA is regulated by post-translational modifications of histones which is called a histone code, and nucleosome remodeling. It also serves as a replacement histone that's imbedded chromatin regions by the HIRA chaperone, after the depletion of the H3.1 during transcription and DNA repair.<ref>https://www.uniprot.org/uniprot/P84243</ref>
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| == Disease ==
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| There have been studies that have identified mutations encoding a K27M substitution and there have also been mutations that encoded
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| GLY 34 to ARG or VAL called the G34R/V substitution. K27M tumors are present in ex: spinal cord, thalamus, pons, brainstem and G34R/V tumors are shown in the cerebral hemispheres. There are mutations in H3.3 that are found in different types of bone tumors like [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446520/ chrondroblastoma] for example and giant cell tumors of the bone. [https://cancerdiscovery.aacrjournals.org/content/3/12/1329.1 Chondroblastoma]arises in children and in young adults in the cartilage of the growth plates of the long bones and is most typically benign.
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| Glioma is another disease caused by the H3F3A mutation, however they are benign or either malignant central nervous system of abnormal growth of tissue from glial cells.
| | == '''Function''' == |
| | * Moving cargo usually from the center of the cell to the margins <br/> |
| | * Involved in cell replication and axonal signaling |
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| [[Image:Glioma_2018_1_4_117_240231_f1.jpg]]
| | == '''Disease''' == |
| | *Charcot Marie Tooth (CMT): Charcot Marie Tooth is one of many diseases that affect the peripheral nervous system. Individuals may suffer physical disabilities due to weakness in transmission of signals firing from the central nervous system |
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| [[Image:a00609f01_resize.jpg]]
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| == Relevance == | | == '''Structural highlights''' == |
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| Histone octamer containing two of H2A, H2B, H3 and H4 and the octamer wraps 147bp of DNA. H3.3 interacts with HIRA which is a chaperone and ZMYND11 when trimethylated at <scene name='75/752263/3wtp/2'>Lysine-36</scene> (color coded dark blue)<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446305/</ref>. HIRA can deposit histones of H3.3 in replicating and non replicating cells. Also in the HIRA complex, Anti slicing factors ASF1a and ASF1b are purified by H3.3. However, when there's a disappearance of HIRA which is responsible for H3.3 deposition, it can cause defects in the early stages of embryogenesis. ZMYND11 also known as BS69 can find H3.3 LYS 36 (H3.3K36me3) by the binding domain of chromatin <ref>https://www.pnas.org/content/112/22/6814</ref>.
| | ;Scene #1: Kinesin structure is composed of eight anti-parallel Beta sheets and three alpha helices on opposite sides <scene name='75/752263/Alpha_beta_sheets/5'> Alpha-beta structure </scene> |
| == Structural highlights ==
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| [https://www.nature.com/articles/srep07115 CENP-A]is a centromere specific variant of Histone H3 and it's controlled in normal cells and its chromosome localization is heavily restricted in the centromere regions. It can be over expressed in cancer cells and also be mislocalized ectopically in the form of heterotypic nucleosomes containing H3.3 <ref>https://www.nature.com/articles/srep07115</ref>. In vitro, the human CENP-A nucleosomes can have two copies each of CENP-A, H2A, H2B and H4 histones <ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585026/</ref>.<scene name='75/752263/Arg_49/1'>ARG 49</scene> is located on H3.3 and is on the E chain (color coded light pink). The significance to this is that ARG 49 of Asf1 is maintained as threonine or glutamic acid. Histone H2B located on chains D and H (color coded dark blue), histone H2A type 1-B/E which is located chains C and G (also color coded dark blue),Histone H3-like centromeric protein A is located on chain A (color coded in the lightest blue),and Histone H4 is located on chains B and F (color coded medium blue) <ref>https://www.rcsb.org/structure/3WTP</ref>.
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| </StructureSection>
| | ;Scene #2: This is the ATP binding site. Upon the binding of phosphate to ADP, ATP is formed giving Kinesin the energy needed to move the cargo one step a head to its destination <scene name='75/752263/Atp_binding_site/5'> ATP-binding site </scene> |
| == References ==
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| <references />
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| 1. Arimura, Y.; Shirayama, K.; Horikoshi, N.; Fujita, R.; Taguchi, H.; Kagawa, W.; Fukagawa, T.; Almouzni, G.; Kurumizaka, H. Crystal structure and stable property of the cancer-associated heterotypic nucleosome containing CENP-A and H3.3. https://www.nature.com/articles/srep07115 (accessed Nov 1, 2020).
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| 2. Cancer Discovery Science Writers. Histone H3.3 Mutations Are Cancer Type-Specific. https://cancerdiscovery.aacrjournals.org/content/3/12/1329.1 (accessed Nov 14, 2020).
| | ;Scene #3: This is the Microtubule-binding site, where Kinesin binds to microtubules for stability <scene name='75/752263/Mt-binding_site/1'> MT-binding site </scene> |
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| 3. Gianno, F.; Antonelli, M.; Ferretti2018, E.; Massimino, M.; Arcella, A.; Giangaspero, F. Pediatric high-grade glioma: A heterogeneous group of neoplasms with different molecular drivers. https://www.jglioma.com/viewimage.asp?img=Glioma_2018_1_4_117_240231_f1.jpg (accessed Nov 16, 2020).
| | ;Scene #4: some patients with CMT show mutation in the p-loop. A missense mutation results in a leucine in place of glutamine affecting signal transmission <scene name='75/752263/Cmt/1'> CMT </scene> |
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| 4. Kallappagoudar, S.; Yadav, R. K.; Lowe, B. R.; Partridge, J. F. Histone H3 mutations--a special role for H3.3 in tumorigenesis? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446520/ (accessed Nov 1, 2020).
| | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. |
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| 5. Morell, N.; Rajani, R. Chondroblastoma - OrthoInfo - AAOS. https://orthoinfo.aaos.org/en/diseases--conditions/chondroblastoma (accessed Nov 16, 2020).
| | </StructureSection> |
| | | == References == |
| 6.panelRuiGuo111LijuanZheng111Juw WonPark2RuituLv1HaoChen1FangfangJiao1WenqiXu1ShirongMu3HongWen45JinsongQiu6ZhentianWang1PengyuanYang1FeizhenWu1JingyiHui3XiangdongFu6XiaobingShi4512Yujiang GenoShi7812YiXing212…YangShi891012, A. links open overlay; RuiGuo111; 1; 11; LijuanZheng111; Juw WonPark2; 2; RuituLv1; HaoChen1; FangfangJiao1; WenqiXu1; ShirongMu3; 3; HongWen45; 4; 5; JinsongQiu6; 6; ZhentianWang1; PengyuanYang1; FeizhenWu1; JingyiHui3; XiangdongFu6; XiaobingShi4512; 12; Yujiang GenoShi7812; 7; 8; YiXing212; YangShi891012; 9; 10; Highlights•BS69/ZMYND11 binds H3.3K36me3 and colocalizes with H3.3K36me3 in gene bodies•BS69 directly interacts with EFTUD2; SummaryBS69 (also called ZMYND11) contains tandemly arranged PHD. BS69/ZMYND11 Reads and Connects Histone H3.3 Lysine 36 Trimethylation-Decorated Chromatin to Regulated Pre-mRNA Processing. https://reader.elsevier.com/reader/sd/pii/S1097276514006777?token=A4FD3B8CDE2F310EA514C66E96DC4489F79C8EA96F6FC878DCD4BFC066FA809C2E83C8A9B57353A53915171AD2491D4C (accessed Nov 16, 2020).
| | #file:///C:/Users/Muna/Desktop/Spring%202021/Advanced%20Biochem/pcbi.1003329.pdf |
| | | #https://www.ncbi.nlm.nih.gov/books/NBK22572/#:~:text=Kinesins%20moving%20along%20microtubules%20usually,surfaces%20of%20some%20eukaryotic%20cells. |
| 7. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Histone H3.3. https://www.uniprot.org/uniprot/P84243 (accessed Nov 1, 2020).
| | #https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Charcot-Marie-Tooth-Disease-Fact-Sheet |
| | | <references/> |
| 8.Yuen, B. T. K.; Knoepfler, P. S. Histone H3.3 mutations: a variant path to cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882088/ (accessed Nov 16, 2020).
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