BibTex format
@article{Noguchi:2026,
author = {Noguchi, Y and Speck, C and Saleh, A},
journal = {Nature Communications},
title = {Structural insights into Sld3-Sld7-dependent Cdc45 loading during replication initiation},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - How DDK phosphorylation primes the MCM2-7 double hexamer (DH) for Sld3-Sld7 binding and Cdc45 loading during helicase activation remained unclear. We define this mechanism through cryo-EM structures of MCM2-7 DH-Sld3-Sld7 (MS) and MCM2-7 DH-Sld3-Sld7-Cdc45 (MSC). Our reinterpretation of published DH maps reveals that the autoinhibitory Mcm4 tail engages sites on both Mcm4 and Mcm6, extending the known autoinhibitory region. Upon DDK-dependent phosphorylation, both sites become accessible. In the context of the MS structure, we discovered that two short Sld3 motifs (MCM recognition domain MRD1 and MRD2) contact now Mcm4 and Mcm6, to read out DH phosphorylation state, while Sld7 anchors the DH at the Mcm2/Mcm6 interface via an MCM-binding helix, and the Sld3 Treslin domain (STD) binds Mcm2. We show that Sld3-Sld7 forms a heterotetramer in solution, but in MS, the Sld7 dimerization domains become separated. In the MSC structure, Cdc45 dislodges the Sld3 STD from Mcm2, allowing Sld3 to position Cdc45 at the Mcm2/Mcm5 interface while MRD1/2 retain their Mcm4/Mcm6 contacts, rationalizing Sld3-dependent Cdc45 recruitment. Mutagenesis of the Sld3 STD-Cdc45 interface disrupts Cdc45 loading, validating this interaction. Together, our data reveal a phosphorylation-encoded mechanism coupling DDK-activated Mcm4/Mcm6 surfaces to distal Cdc45 placement, explaining how firing factors choreograph the DH-to-CMG transition.
AU - Noguchi,Y
AU - Speck,C
AU - Saleh,A
PY - 2026///
SN - 2041-1723
TI - Structural insights into Sld3-Sld7-dependent Cdc45 loading during replication initiation
T2 - Nature Communications
ER -