XPD Helicase (3CRV)
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| - | == '''XPD Helicase''' == | + | <StructureSection load='3CRV' size='450' side='right' scene='72/728075/Reset/2' caption='XPD helicase, 3CRV'> |
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| + | == XPD Helicase == | ||
| + | ''Xeroderma pigmentosum'' group D '''(XPD) helicase''' is a subunit of [http://proteopedia.org/wiki/index.php/Category:Tfiih Transcription Factor IIH (TFIIH)], which aids in [http://proteopedia.org/wiki/index.php/Category:Transcription_initiation transcription initiation] and DNA repair. XPD helicse unwinds DNA, allowing other [http://proteopedia.org/wiki/index.php/Category:Dna-repair DNA repair enzymes] to access and correct damaged regions in the DNA. XPD helicase helps to fix DNA damaged by ultraviolet (UV) light radiation; therefore mutations in XPD helicase results in diseases characterized by light sensitivity. | ||
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| + | == Structure == | ||
| + | XPD helicase's catalytic core (<scene name='72/728075/Domains/3'>Figure 1</scene>) is composed of four domains, HD1 (green), HD2 (red), 4FeS (brown), and Arch (blue), and six motifs. The HD1 and HD2 domains form the ATP-Binding Interface.The 4FeS (pink) domain contains Cysteines 88, 102, 105, and 137 that bind the Sulfur-Iron cluster; this domain helps to detect DNA damage. Single stranded DNA (ssDNA) binding is facilitated by the 4FeS domain's Fe-S region, and a channel is formed with HD1 and Arch Domains to form a passage way for the ssDNA. Positively charged residues along the channel are paired with negatively charged residues to allow subsequent ssDNA binding and movement along the ssDNA. The HD2 and Arch domain form the HD2 gateway, which is associated with sensing bulky DNA damage as well. The motif's (<scene name='72/728075/Motifs/3'>Figure 2</scene>), I (31-60, red), II (177-186, blue), III (317-327, green), IV (394-408, brown), V (439-455, purple) and VI (501-517, orange), all play a role in both ATP and DNA binding. Motif's I, II, V, and VI all form the ATP binding site at the HD1 and HD2 interface (<scene name='72/728075/Atp_binding/2'>Figure 3</scene>). Motif's IV, V, and VI within the HD2 domain form the gateway channel for DNA binding (<scene name='72/728075/Hd2_gate/2'>Figure 4</scene>)<ref name="Lifuss">PMID: 18510924 </ref>. | ||
| + | (<scene name='72/728075/Reset/2'>Reset Protein</scene>) | ||
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== Function == | == Function == | ||
| + | XPD helicase is an essential subunit of the general transcription factor IIH (TFIIH), which is a complex that, along with other general transcription factors, helps to initiate transcription and repair damaged DNA <ref name="Mydikova">PMID: 20429618</ref>. XPD helicase helps to stabilize the structure of TFIIH but also plays a functional role in repairing DNA as a helicase enzyme <ref name="Lifuss">PMID: 18510924 </ref>. Helicases are enzymes that unwind double-stranded DNA into single-stranded DNA so that other enzymes, like polymerases, can act upon the DNA <ref name="Tuteja">PMID: 15128295 </ref>. In the context of DNA repair, helicases unwind DNA and other enzymes remove the damaged DNA and replace it with the complementary nucleotides based on the other DNA sequence. When DNA is exposed to UV radiation, adjacent nucleotide bases, often thymines, can react and form bulky pyrimidine dimers, which can block enzymes that work on DNA <ref name="Vink">PMID: 11809365 </ref>. For example, during DNA replication, [http://proteopedia.org/wiki/index.php/Category:Thymine_Dimers thymine dimers] do not fit into the active site of DNA polymerases smoothly, sometimes resulting in mismatched nucleotides. To fix this type of damage on single strands of DNA, cells employ a process called [http://proteopedia.org/wiki/index.php/Category:Nucleotide_excision_repair nucleotide excision repair (NER)] <ref name="Lifuss">PMID: 18510924 </ref>. This is the type of DNA repair that TFIIH, with the help of the XPD helicase subunit, carries out to remove the damaged DNA. | ||
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| + | Breaking the hydrogen bonds that hold the two DNA strands together requires energy, so XPD helicase is dependent on ATP <ref name="Buechner">PMID: 24338567 </ref>. The ATP-dependent helicase activity of XPD helicase, however is only required for NER, even though TFIIH participates in both repair and transcription initiation <ref name="Kuper">PMID: 25268380 </ref>. XPD helicase not only unravels the DNA around the damage, but also helps TFIIH in recognizing bulky lesions in DNA <ref>DOI 10.1093/nar/gkw102 </ref>. The DNA is then threaded through the central pore of XPD helicase, which then opens up the double helix. | ||
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== Disease == | == Disease == | ||
| - | + | The NER pathway consists of 28 genes, three of which are part of TFIIH, and mutations in many of these are associated with a set of diseases that are similar but have marked differences <ref name="Kraemer">PMID: 17276014 </ref>. Mutations in XPD helicase are associated with three distinct diseases: [https://ghr.nlm.nih.gov/condition/cockayne-syndrome Cockayne Syndrome (CS)], [https://ghr.nlm.nih.gov/condition/xeroderma-pigmentosum Xeroderma Pigmentosum (XP)], and [https://ghr.nlm.nih.gov/condition/trichothiodystrophy trichothiodystrophy (TTD)] <ref>DOI 10.1093/nar/gkv472</ref>. The common symptom between these diseases is sensitivity to UV light because of defects in the repair system that fixes mutations caused by UV radiation <ref name="Lifuss">PMID: 18510924 </ref>. | |
| - | == | + | CS is characterized by short stature, signs of premature aging, failure to gain weight, impaired development of the nervous system, and photosensitivity <ref name="Nance">PMID: 1308368 </ref>. XP is characterized by extreme sensitivity to sunlight and a higher risk of skin cancer. Some XP patients have neurological degeneration, which can be explained by the fact that neurons do not divide, and mutations that are not corrected by NER could accumulate and eventually lead to cell death <ref name="Kraemer">PMID: 17276014 </ref>. TTD is characterized by sparse and brittle hair, pregnancy-induced high blood pressure, intellectual disabilities, a higher risk of recurrent respiratory infections, and photosensitivity <ref name="Hashimoto">PMID: 19808800 </ref>. It has been proposed that specific mutations in XPD helicase affect the transcription activities of TFIIH more than its repair activities, resulting in development issues that lead to intellectual disabilities <ref name="Kraemer">PMID: 17276014 </ref>. Interestingly, only XP has been found to be associated with an increased risk of skin cancer; studies are being conducted to determine why some mutations in XPD helicase result in a higher risk of skin cancer and others do not. Different types of mutations in XPD helicase as well as interactions between XPD helicase mutations and defects in other NER proteins can result in these different diseases. Due to the complexity of these interactions, little is known about the molecular basis for the differences in these diseases <ref name="Kraemer">PMID: 17276014 </ref>. |
| - | == Structural highlights == | ||
| - | 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. | ||
| - | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||
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