Volume 67, Issue 2, Pages (July 2017)

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Volume 67, Issue 2, Pages 168-179 (July 2017) Unique Roles of the Non-identical MCM Subunits in DNA Replication Licensing  Yuanliang Zhai, Ningning Li, Hanlun Jiang, Xuhui Huang, Ning Gao, Bik Kwoon Tye  Molecular Cell  Volume 67, Issue 2, Pages 168-179 (July 2017) DOI: 10.1016/j.molcel.2017.06.016 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Subunit-Specific Structural Features of the Mcm2–7 Subunits (A) Schematic illustration of domain organization and subunit-specific features of the S. cerevisiae Mcm2–7 subunits compared to the archaeal MCM (Ss, Sulfolobus solfatoricus). NTE, N-terminal extension; NTD-A, N-terminal domain A; OB, oligonucleotide-binding fold; ZF, zinc finger; CTD, C-terminal domain; CTE, C-terminal extension; NTI, NTD insertion; N-C linker, NTD CTD linker; CTI, CTD insertion; WH, wing helix. (B–D) Side-by-side structural comparison of Mcm2–7 subunits from CM (PDB: 5h7i) (B), OCCM (PDB: 5udb) (C), and Mcm2–7 DH (PDB: 3ja8) (D) using the OB domain as a reference for alignment. Not shown are subunit structures of Mcm2–7 single hexamer because of their similarity to CM. Molecular Cell 2017 67, 168-179DOI: (10.1016/j.molcel.2017.06.016) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Comparison of the Overall Structures of the Mcm2–7 Complexes Related to Replication Licensing (A–P) Cryo-EM maps, shown in surface representation, of the Mcm2–7 single hexamer (EMD: 6674) (A–D), the Cdt1-MCM heptamer (EMD: 6671) (E–H), OCCM (EMD: 8540, only Cdt1-Mcm2-7 is shown) (I–L), and Mcm2–7 DH (EMD: 6338, only half of DH is shown) (M–P). Subunits are color coded as indicated by the labels. Top (A, E, I, and M) and side views (all other panels) are shown. Visual effect with depth cueing was applied such that Mcm7 in the back side is hardly visible in (B), (F), and (J). Molecular Cell 2017 67, 168-179DOI: (10.1016/j.molcel.2017.06.016) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 Rearrangements of the MCM CTEs during MCM Loading (A and B) Front and back views of the OCCM structure (PDB: 5udb). Highlighted in colors are CTEs in (A) and the gate-forming subunits Mcm2 and Mcm5 in (B). (C) Contact surfaces created by ORC and Cdc6 for WHDs of M3 and M7. (D) Cdc6 and DNA contact points in OC. (E–G) Steric hindrance for MCM loading imposed by the CTEs from Mcm4, Mcm5, and Mcm6 of the Cdt1-MCM heptamer (PDB: 5h7i). The structures of the Cdt1-MCM and the OCCM were superimposed by aligning the Mcm2-CTD. (E) Side view shows the superimposed structures of OC-DNA (in gray) derived from OCCM and the cWHDs (color coded) from Cdt1-MCM heptamer. (F) Top view shows the aligned structures in (E). Outline traces the contour of OC. During the transition from Cdt1-Mcm to OCCM, the cWHDs of Mcm4, 5, and 6 undergo translocation as indicated by arrows, while the CTEs of Mcm3 and 7 form structured cWHD. (G) The putative pathway of Mcm5-cWHD translocation in transitioning from Cdt1-MCM to OCCM is shown. The lower position indicates the initial location of Mcm5-WHD in the Cdt1-MCM using Mcm2-CTD as reference for alignment with OCCM; the upper position is its intermediate location using Mcm5-CTD as reference for alignment. Further translation of the Mcm5-WHD is suggested as the arrow-headed direction. Molecular Cell 2017 67, 168-179DOI: (10.1016/j.molcel.2017.06.016) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 4 The Conformational Changes of Cdt1-CTD and Mcm6-cWHD during OCCM Formation (A) Superimposition of Cdt1 in Cdt1-MCM (gray) (PDB: 5h7i) and in OCCM (green) (PDB: 5udb) in schematically organized domains. (B and C) The relative positions of Cdt1-CTD (green) with Mcm6-WHD (blue) in Cdt1-MCM (B) and OCCM (C). Molecular Cell 2017 67, 168-179DOI: (10.1016/j.molcel.2017.06.016) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 5 Modeling of MCM-DH DNA Complex (A) Cut-away view of the density map of the MCM-DH with a piece of origin DNA ARS305 modeled in the central channel. The base pairings of the nucleotides were adjusted according to the spatial restriction of the MCM central channel. The origin DNA embedded in the region of the hexamer interface is shown in magnified view. (B) Model for initial origin DNA melting, adapted from Li et al. (2015). The MCM-DH structure refined with NCS restraints was used to model the MCM-DH-DNA complex. Double-stranded DNA (dsDNA) structures with the sequence of the MCM-binding site at ARS305 were inserted into the central channel of each MCM hexamer. Specifically, the dsDNA in each hexamer was rotated along its longitudinal axis to minimize the protein-DNA steric clashes with PyMOL (http://www.pymol.org). Due to the kink at the interface between the two hexamers, fully base-paired dsDNA cannot be accommodated at this region. Therefore, the dsDNA structure at the interface was remodeled by ModeRNA (Rother et al., 2011) and inserted into the central channel. Finally, A 5,000-step energy minimization by ENCAD (Levitt, 1983; Levitt et al., 1995) was performed to further refine the complex structure by eliminating the remaining clashes. Molecular Cell 2017 67, 168-179DOI: (10.1016/j.molcel.2017.06.016) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 6 The Acrobat Model for the Independent Loading of the Two MCM Heptamers by a Single ORC (A) Cartoon representations of structural features of Mcm2–7 subunits, OC and Cdt1. (B) Loading of the first MCM heptamer by direct anchoring of Mcm3cWHD to OC, followed by Mcm7-cWHD, Mcm6-cWHD, and Mcm4-cWHD, to form OCCM. Flexible CTEs refer to the unresolved CTE structures presumably due to the flexible linkers to the cWHDs. (C) Recruitment of the second MCM heptamer by the reciprocal interactions of the flexible Mcm5-NTEs and the Mcm7-NTDs from head-to-head MCM rings. Molecular Cell 2017 67, 168-179DOI: (10.1016/j.molcel.2017.06.016) Copyright © 2017 Elsevier Inc. Terms and Conditions