XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations.
Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.
Department of Molecular Biology, Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Li
L
Fan
Jill O
JO
Fuss
Quen J
QJ
Cheng
Andrew S
AS
Arvai
Michal
M
Hammel
Victoria A
VA
Roberts
Priscilla K
PK
Cooper
John A
JA
Tainer
D019843:Archaeal Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D003057:Cockayne Syndrome / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D007506:Iron-Sulfur Proteins / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein; D016945:Sulfolobus acidocaldarius / Q000201:enzymology*; D054463:Trichothiodystrophy Syndromes / Q000235:genetics / Q000378:metabolism; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism; D051759:Xeroderma Pigmentosum Group D Protein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D019843:Archaeal Proteins; D007506:Iron-Sulfur Proteins; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein