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Summary

Chromatin remodeling complexes (SRCAP-C) mediate the exchange of H2A.Z with H2A, leading to the incorporation of H2A.Z-H2B dimers into chromatin through a step-by-step manner. Here, we determined the crystal structure of the N-terminal region (531-560) of the catalytic subunit of SRCAP-C, termed SRCAP-Z domain, in complex with the engineered single-chain H2B-H2A.Z (scH2B-H2A.Z) at 2.53 Å resolution. In the crystal structure, two molecules of scH2B-H2A.Z and one molecule of SRCAP-Z form a sandwich-like architecture. Histones form typical histone fold and SRCAP-Z domain adopts a short 3 ₁₀ helix. In details, Val551, Leu554, and Leu555 of the SRCAP-Z 3 ₁₀ helix specifically recognize the αC helix of H2A.Z through hydrophobic interactions. The particular recognition has been validated in vitro by MBP-pulldown and isothermal titration calorimetry (ITC) experiments, and the MBP-pulldown assay results demonstrated that mutations in specific amino acids of SRCAP-Z attenuated its interaction with H2A.Z-H2B dimer. Finally, we demonstrated that SRCAP-Z recognizes H2A.Z-H2B dimer with a conservative structural basis and facilitates the nucleosome assembly by its chaperone activity.

Highlights

• Firstly, we determined the structure of the SRCAP-Z domain/scH2A.Z-H2B complex at 2.53 Å resolution.

• Second, our results support a mechanism of H2A.Z-H2B/H2A-H2B exchange model in which YL1 enriches H2A.Z/H2B around nucleosomes, presenting them to SRCAP, which mediates the exchange of H2A.Z/H2B with H2A/H2B.

• Third, SRCAP-Z recognition of H2A.Z-H2B dimer is structurally conserved.

• Fourth, a distinct sandwich-like architecture: SRCAP-Z adopts a 3 ₁₀ helix that inserts precisely between H2A.Z and H2B, forming a stable, unexpected structural module.