The three-dimensional structure of the HRDC domain and implications for the Werner and Bloom syndrome proteins.
BACKGROUND
The HRDC (helicase and RNaseD C-terminal) domain is found at the C terminus of many RecQ helicases, including the human Werner and Bloom syndrome proteins. RecQ helicases have been shown to unwind DNA in an ATP-dependent manner. However, the specific functional roles of these proteins in DNA recombination and replication are not known. An HRDC domain exists in both of the human RecQ homologues that are implicated in human disease and may have an important role in their function.


RESULTS
We have determined the three-dimensional structure of the HRDC domain in the Saccharomyces cerevisiae RecQ helicase Sgs1p by nuclear magnetic resonance (NMR) spectroscopy. The structure resembles auxiliary domains in bacterial DNA helicases and other proteins that interact with nucleic acids. We show that a positively charged region on the surface of the Sgs1p HRDC domain can interact with DNA. Structural similarities to bacterial DNA helicases suggest that the HRDC domain functions as an auxiliary domain in RecQ helicases. Homology models of the Werner and Bloom HRDC domains show different surface properties when compared with Sgs1p.


CONCLUSIONS
The HRDC domain represents a structural scaffold that resembles auxiliary domains in proteins that are involved in nucleic acid metabolism. In Sgs1p, the HRDC domain could modulate the helicase function via auxiliary contacts to DNA. However, in the Werner and Bloom syndrome helicases the HRDC domain may have a role in their functional differences by mediating diverse molecular interactions.
Liu
Z
Z
European Molecular Biology Laboratory, Heidelberg, Germany.
Macias
M J
MJ
Bottomley
M J
MJ
Stier
G
G
Linge
J P
JP
Nilges
M
M
Bork
P
P
Sattler
M
M
D000251:Adenosine Triphosphatases / Q000737:chemistry*; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D001816:Bloom Syndrome / Q000201:enzymology; D017124:Conserved Sequence; D004265:DNA Helicases / Q000737:chemistry*; D004722:Endoribonucleases / Q000737:chemistry*; D005090:Exodeoxyribonucleases; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D053484:RecQ Helicases; D011994:Recombinant Proteins / Q000737:chemistry; D043244:Ribonuclease III; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012984:Software; D013816:Thermodynamics; D014898:Werner Syndrome / Q000201:enzymology; D000071657:Werner Syndrome Helicase
D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D004722:Endoribonucleases; D005090:Exodeoxyribonucleases; C468367:RNT1 protein, S cerevisiae; D043244:Ribonuclease III; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; C090472:SGS1 protein, S cerevisiae; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase