The Human Mixed Lineage Leukemia 5 (MLL5), a Sequentially and Structurally Divergent SET Domain-Containing Protein with No Intrinsic Catalytic Activity.
Mixed Lineage Leukemia 5 (MLL5) plays a key role in hematopoiesis, spermatogenesis and cell cycle progression. Chromatin binding is ensured by its plant homeodomain (PHD) through a direct interaction with the N-terminus of histone H3 (H3). In addition, MLL5 contains a Su(var)3-9, Enhancer of zeste, Trithorax (SET) domain, a protein module that usually displays histone lysine methyltransferase activity. We report here the crystal structure of the unliganded SET domain of human MLL5 at 2.1 Å resolution. Although it shows most of the canonical features of other SET domains, both the lack of key residues and the presence in the SET-I subdomain of an unusually large loop preclude the interaction of MLL5 SET with its cofactor and substrate. Accordingly, we show that MLL5 is devoid of any in vitro methyltransferase activity on full-length histones and histone H3 peptides. Hence, the three dimensional structure of MLL5 SET domain unveils the structural basis for its lack of methyltransferase activity and suggests a new regulatory mechanism.
Inserm U1054, Centre de Biochimie Structurale, Montpellier, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier, France.|Université de Montpellier, Montpellier, France.
Sarah
S
Mas-Y-Mas
Inserm U1054, Centre de Biochimie Structurale, Montpellier, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier, France.|Université de Montpellier, Montpellier, France.
Marta
M
Barbon
Université de Montpellier, Montpellier, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
Catherine
C
Teyssier
Inserm U1054, Centre de Biochimie Structurale, Montpellier, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier, France.|Université de Montpellier, Montpellier, France.
Hélène
H
Déméné
Sorbonne Universités, UPMC Université Paris 06, CNRS, Laboratoire de Biologie du Développement de Villefranche-sur-Mer, Observatoire Océanologique de Villefranche-sur-Mer, Villefranche-sur-Mer, France.
João E
JE
Carvalho
OPPF-UK, Research Complex at Harwell, Rutherford Appleton Laboratory, Oxfordshire, OX11 0FA, United Kingdom.
Louise E
LE
Bird
CCP4, Research Complex at Harwell, Rutherford Appleton Laboratory, Oxfordshire, OX11 0FA, United Kingdom.
Andrey
A
Lebedev
Centro Nacional de Pesquisa em Energia e Materiais, Laboratório Nacional de Biociências, Campinas, SP, Brazil.
Juliana
J
Fattori
Sorbonne Universités, UPMC Université Paris 06, CNRS, Laboratoire de Biologie du Développement de Villefranche-sur-Mer, Observatoire Océanologique de Villefranche-sur-Mer, Villefranche-sur-Mer, France.
Michael
M
Schubert
Inserm U1054, Centre de Biochimie Structurale, Montpellier, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier, France.|Université de Montpellier, Montpellier, France.
Christian
C
Dumas
Inserm U1054, Centre de Biochimie Structurale, Montpellier, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier, France.|Université de Montpellier, Montpellier, France.
William
W
Bourguet
Inserm U1054, Centre de Biochimie Structurale, Montpellier, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier, France.|Université de Montpellier, Montpellier, France.|Centro Nacional de Pesquisa em Energia e Materiais, Laboratório Nacional de Biociências, Campinas, SP, Brazil.
Albane
A
le Maire
D000595:Amino Acid Sequence; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D000072417:Protein Domains
D004268:DNA-Binding Proteins; C460660:KMT2E protein, human