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Review
. 2008 Apr;18(2):243-57.
doi: 10.1016/j.sbi.2008.01.007. Epub 2008 Mar 10.

On helicases and other motor proteins

Eric J Enemark  1 , Leemor Joshua-Tor
Affiliations
Review

On helicases and other motor proteins

Eric J Enemark et al. Curr Opin Struct Biol. 2008 Apr.

Abstract

Helicases are molecular machines that utilize energy derived from ATP hydrolysis to move along nucleic acids and to separate base-paired nucleotides. The movement of the helicase can also be described as a stationary helicase that pumps nucleic acid. Recent structural data for the hexameric E1 helicase of papillomavirus in complex with single-stranded DNA and MgADP has provided a detailed atomic and mechanistic picture of its ATP-driven DNA translocation. The structural and mechanistic features of this helicase are compared with the hexameric helicase prototypes T7gp4 and SV40 T-antigen. The ATP-binding site architectures of these proteins are structurally similar to the sites of other prototypical ATP-driven motors such as F1-ATPase, suggesting related roles for the individual site residues in the ATPase activity.

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Figures

Figure 1
Figure 1
Selected hexameric ATPases. A) F1-ATPase (PDB code 1BMF) as viewed from the membrane side of the complex. The individual subunits are color-coded: α-subunits in red, yellow, and blue; β-subunits in orange, green, and purple; and the central γ-subunit in cyan. Nucleotides are depicted in stick representation. B) Bacteriophage T7gp4 (PDB code 1E0J) viewed from the proposed DNA entrance side of the complex. The individual subunits are color-coded. Nucleotides are depicted in stick representation, and the arginine finger residues (R522) are drawn as black sticks. The central DNA-binding loops (loop II) are depicted with a larger radius. C) Papillomavirus E1 DNA complex (PDB code 2GXA). The individual subunits are color-coded with the central single-stranded DNA in cyan. The arginine finger residues (R538) are drawn in black stick representation. Nucleotides that interact with R538 (“ATP-type”) are drawn in red; nucleotides that do not interact with R538 but still interact with the adjacent subunit (“ADP-type”) are drawn in blue; and the nucleotide which only interacts with one subunit (“apo-type”) is drawn in green. D) DnaB bound to the helicase-binding domain of DnaG (PDB code 2R6A) viewed from the proposed DNA exit side of the complex (primase domain side). The six DnaB subunits are color-coded, and three DnaG helicase-binding domains are in grey. All figures were prepared with Bobscript[92,93] and rendered with Raster3D[94].
Figure 2
Figure 2
Depiction of the coordinated escort mechanism for DNA translocation by sequential ATP hydrolysis. The DNA-binding hairpins of each subunit collectively migrate downward as the ATP cycle sequentially permutes among the sunbunit interfaces. Each DNA-binding hairpin maintains continuous contact with one nucleotide of DNA and escorts it through the hexameric channel. Every sixth nucleotide of DNA is colored black and is escorted by the purple hairpin. Structural figures were prepared with Bobscript [92,93] and rendered with Raster3D[94].
Figure 3
Figure 3
Sequence alignment of archaeal (top) and eukaryotic (grouped by type) MCM proteins. For comparison, the SF3 helicase BPV E1 and the BchI[95] subunit of Mg chelatase (h2i-containing AAA+ protein) is provided at the bottom. The helix-2 insert aligns with a BPV E1 phenylalanine that interacts with the sugar moiety of the ssDNA in the crystal structure (purple). For E1, an acidic and basic residue on the DNA-binding hairpin (ps1β) form an inter-subunit salt-bridge to “staircase” the hairpins (pink). In MCM proteins, no acidic residue is available on the ps1β to “staircase” a conserved lysine that is required for helicase activity[52]. Potential “staircasing” residues on the helix-2 insert (pink) are conserved in all MCM proteins identified as a component of a helicase-active assembly (archaeal or MCM4/6/7). Consistent differences among the eukaryotic subunits involving basic subunits are highlighted in yellow. A conserved glycine of the ps1β likely forms a glycine β-turn that would structurally align with H507 of E1. Hence, the conserved ps1β lysine of MCM proteins is anticipated to align with E1 R506 (cyan).
Figure 4
Figure 4
Salt-bridge tethered ATP-binding site. The binding site consists of a consistently structured left side involving the Walker A and Walker B motifs. The right side includes three basic residues. A) F1-ATPase active site with the β-subunit in yellow and the α-subunit in cyan. B) Papillomavirus E1 with one subunit in yellow and the adjacent subunit in cyan. A chloride ion in the γ-phosphate position is colored green. C) PcrA active site with RecA-like domain 1 in yellow and RecA-like domain 2 in cyan. D, E) Stereoviews of the F1-ATPase configuration bound to ADP-BeF3 (PDB code 1W0J) and the E1 ATP-type configuration (PDB code 2GXA). The subunits are color coded as above. F) Structural overlay of the E1 ATP type configuration with the F1-ATPase configuration. The E1 structure is in color, and the F1-ATPase is in grey. Structural figures were prepared with Bobscript [92,93] and rendered with Raster3D[94].
Figure 5
Figure 5
Glutamine-tethered ATP-binding site. The binding site consists of a consistently structured left side involving the Walker A and Walker B motifs. The other side of the site consists of a highly conserved glutamine and two basic residues. A) Schematic representation of the ATP configuration for T7gp4 with one subunit in yellow and the adjacent subunit in cyan. B) Schematic of the SF2 helicase RecQ with RecA-like domain 1 in yellow and RecA-like domain 2 in cyan. C, D) Stereoviews of the T7gp4 AMP-PNP (PDB code 1E0J) and the RecQ ATP-γS configurations (PDB code 1OYY). The first tether “mediator” position is generally aromatic (conserved tyrosine in DnaB), and the second position is occupied by either histidine or glutamine (conserved glutamine in DnaB). Structural figures were prepared with Bobscript[92,93] and rendered with Raster3D[94].
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