Abstract
Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers. Mutations in the YEATS domain have been recently reported as a cause of MLLT1 aberrant reader function. However, structural basis for the reported alterations in affinity for acetyled/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that such alteration not only altered the binding interface for acetylated/acylated histones, but the sequence alterations in the T1 loop may enable dimeric assembly consistent inducing self-association behavior. Nevertheless, we show that also the MLLT1 mutants can be targeted by developed acetyllysine mimetic inhibitors with affinities similarly to wild type. Our report provides a structural basis for the altered behaviors and potential strategy for targeting oncogenic MLLT1 mutants.
Competing Interest Statement
Allyn T. Londregan and Dafydd R. Owen are employees of Pfizer.
ABBREVIATIONS
- YEATS domain
- The Yaf9, ENL, AF9, Taf14, Sas5 (YEATS) domain;
- ENL
- eleven-nineteen-leukemia protein;
- MLLT1
- myeloid/lymphoid or mixed-lineage leukemia translocated to, chromosome 1 protein;
- AF9
- ALL1-fused gene from chromosome 9 protein;
- MLLT3
- myeloid/lymphoid or mixed-lineage leukemia translocated to chromosome 3 protein.