Multivalency of nucleosome recognition by LEDGF

Author:

Koutná Eliška12ORCID,Lux Vanda1ORCID,Kouba Tomáš1ORCID,Škerlová Jana1ORCID,Nováček Jiří3ORCID,Srb Pavel1ORCID,Hexnerová Rozálie1ORCID,Šváchová Hana1,Kukačka Zdeněk4ORCID,Novák Petr4ORCID,Fábry Milan1,Poepsel Simon56ORCID,Veverka Václav12ORCID

Affiliation:

1. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Prague 160 00 , Czech Republic

2. Department of Cell Biology, Faculty of Science, Charles University , Prague 128 00 , Czech Republic

3. CEITEC , Brno 625 00 , Czech Republic

4. Institute of Microbiology of the Czech Academy of Sciences , Prague 142 20 , Czech Republic

5. Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne , Cologne 509 31 , Germany

6. Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne , Cologne 509 31 , Germany

Abstract

Abstract Eukaryotic transcription is dependent on specific histone modifications. Their recognition by chromatin readers triggers complex processes relying on the coordinated association of transcription regulatory factors. Although various modification states of a particular histone residue often lead to differential outcomes, it is not entirely clear how they are discriminated. Moreover, the contribution of intrinsically disordered regions outside of the specialized reader domains to nucleosome binding remains unexplored. Here, we report the structures of a PWWP domain from transcriptional coactivator LEDGF in complex with the H3K36 di- and trimethylated nucleosome, indicating that both methylation marks are recognized by PWWP in a highly conserved manner. We identify a unique secondary interaction site for the PWWP domain at the interface between the acidic patch and nucleosomal DNA that might contribute to an H3K36-methylation independent role of LEDGF. We reveal DNA interacting motifs in the intrinsically disordered region of LEDGF that discriminate between the intra- or extranucleosomal DNA but remain dynamic in the context of dinucleosomes. The interplay between the LEDGF H3K36-methylation reader and protein binding module mediated by multivalent interactions of the intrinsically disordered linker with chromatin might help direct the elongation machinery to the vicinity of RNA polymerase II, thereby facilitating productive elongation.

Funder

Czech Science Foundation

Ministry of Education of the Czech Republic

European Regional Development Fund

Chemical Biology for Drugging Undruggable Targets

Charles University

European Regional Development

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Genetics

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