Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase.

Abstract:

:SET8 (also known as PR-SET7) is a histone H4-Lys-20-specific methyltransferase that is implicated in cell-cycle-dependent transcriptional silencing and mitotic regulation in metazoans. Herein we report the crystal structure of human SET8 (hSET8) bound to a histone H4 peptide bearing Lys-20 and the product cofactor S-adenosylhomocysteine. Histone H4 intercalates in the substrate-binding cleft as an extended parallel beta-strand. Residues preceding Lys-20 in H4 engage in an extensive array of salt bridge, hydrogen bond, and van der Waals interactions with hSET8, while the C-terminal residues bind through predominantly hydrophobic interactions. Mutational analysis of both the substrate-binding cleft and histone H4 reveals that interactions with residues in the N and C termini of the H4 peptide are critical for conferring substrate specificity. Finally, analysis of the product specificity indicates that hSET8 is a monomethylase, consistent with its role in the maintenance of Lys-20 monomethylation during cell division.

journal_name

Genes Dev

journal_title

Genes & development

authors

Couture JF,Collazo E,Brunzelle JS,Trievel RC

doi

10.1101/gad.1318405

subject

Has Abstract

pub_date

2005-06-15 00:00:00

pages

1455-65

issue

12

eissn

0890-9369

issn

1549-5477

pii

gad.1318405

journal_volume

19

pub_type

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