No abstract

The first step in molybdenum cofactor biosynthesis, the conversion of 5-GTP to precursor Z, an oxygen-sensitive tetrahydropyranopterin is catalyzed by the S-adenosylmethionine ( iron-sulfur ͉ radicals ͉ molybdenum cofactor ͉ GTP cyclohydrolase

DNA damage recognition by the nucleotide excision repair pathway requires an initial step identifying helical distortions in the DNA and a proofreading step verifying the presence of a lesion. This proofreading step is accomplished in eukaryotes by the TFIIH complex. The critical damage recognition component of TFIIH is the XPD protein, a DNA helicase that unwinds DNA and identifies the damage. Here, we describe the crystal structure of an archaeal XPD protein with high sequence identity to the human XPD protein that reveals how the structural helicase framework is combined with additional elements for strand separation and DNA scanning. Two RecA-like helicase domains are complemented by a 4Fe4S cluster domain, which has been implicated in damage recognition, and an α-helical domain. The first helicase domain together with the helical and 4Fe4S-cluster–containing domains form a central hole with a diameter sufficient in size to allow passage of a single stranded DNA. Based on our results, we suggest a model of how DNA is bound to the XPD protein, and can rationalize several of the mutations in the human XPD gene that lead to one of three severe diseases, xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy.

Edited by Wilhelm JustKeywords: ATPases Associated with diverse cellular Activities p47 UFD1-NPL4 UBXD1 Inclusion Body Myopathy with Pagets disease of the bone and Fronto-temporal Dementia a b s t r a c t p97 (also known as Cdc48, Ter94, and VCP) is an essential, abundant and highly conserved ATPase driving the turnover of ubiquitylated proteins in eukaryotes. Even though p97 is involved in highly diverse cellular pathways and processes, it exhibits hardly any substrate specificity on its own. Instead, it relies on a large number of regulatory cofactors controlling substrate specificity and turnover. The complexity as well as temporal and spatial regulation of the interactions between p97 and its cofactors is only beginning to be understood at the molecular level. Here, we give an overview on the structural framework of p97 interactions with its cofactors, the emerging principles underlying the assembly of complexes with different cofactors, and the pathogenic effects of disease-associated p97 mutations on cofactor binding.