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XPD Helicase (3CRV): Difference between revisions

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== XPD Helicase ==
== 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.   
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.   
== Structure ==
XPD helicase's catalytic core (<scene name='72/728075/Domains/2'>Figure 1</scene>) is composed of four domains, HD1 (green), HD2 (red), 4FeS (brown), and Arch (blue) domains, and six motifs. The HD1 and HD2 domains form the ATP-Binding Interface.The 4FeS domain contains Cysteines 88, 102, 105, and 137 in which the Sulfur-Iron binding occurs (pink), the complex has the role of detecting DNA damage. 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. HD2 domain and the Arch domain form the HD2 gateway which is associated with sensing bulky DNA damage as well. The motif's (<scene name='72/728075/Motifs/2'>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/1'>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/1'>Figure 4</scene>). [http://www.omim.org/entry/601675 TTD1]  <ref>DOI 10.1093/nar/gku989 </ref>.
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== Function ==
== Function ==
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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>.
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>.     
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>.     
== Structure ==
XPD helicase's catalytic core (<scene name='72/728075/Domains/2'>Figure 1</scene>) is composed of four domains, HD1 (green), HD2 (red), 4FeS (brown), and Arch (blue) domains, and six motifs. The HD1 and HD2 domains form the ATP-Binding Interface.The 4FeS domain contains Cysteines 88, 102, 105, and 137 in which the Sulfur-Iron binding occurs (pink), the complex has the role of detecting DNA damage. 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. HD2 domain and the Arch domain form the HD2 gateway which is associated with sensing bulky DNA damage as well. The motif's (<scene name='72/728075/Motifs/2'>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/1'>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/1'>Figure 4</scene>). [http://www.omim.org/entry/601675 TTD1]  <ref>DOI 10.1093/nar/gku989 </ref>.
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