G3DSA:2.170.270.10

SET domain

CATH-Gene3D entry
Member databaseCATH-Gene3D
CATH-Gene3D typehomologous superfamily

Description
Imported from IPR046341

The SET domain is a 130 to 140 amino acid, evolutionary well conserved sequence motif that was initially characterised in the Drosophila proteins Su(var)3-9, Enhancer-of-zeste and Trithorax
[7, 4]
. In eukaryotic organisms, it appears in proteins with an important role in regulating chromatin-mediated gene transcriptional activation and silencing. In viruses,bacteria and archaea, its function is not clear yet
[5]
.

This superfamily includes eukaryotic proteins with histone methyltransferase activity, which requires the combination of the SET domain with the adjacent cysteine-rich regions, one located N-terminally (pre-SET) and the other posterior to the SET domain (post-SET). Post- and pre- SET regions seem then to play a crucial role when it comes to substrate recognition and enzymatic activity
[1, 6]
. Other SET domain-containing proteins function as transcription factors (such as PR domain zinc finger protein 1 from humans
[9]
).

The structure of the SET domain and the two adjacent regions pre-SET and post-SET have been solved
[3, 10, 8]
. The SET domain structure is all-β, but consists only in sets of few short strands composing no more than a couple of small sheets. Consequently the SET structure is mostly defined by turns and loops. An unusual feature is that the SET core is made up of two discontinuous segments of the primary sequence forming an approximate L-shape
[2, 1, 6]
. Two of the most conserved motifs in the SET domain are constituted by a stretch at the C-terminal containing a strictly conserved tyrosine residue and a preceding loop inside which the C-terminal segment passes forming a knot-like structure, but not quite a true knot. These two regions have been proven to be essential for SAM binding and catalysis, particularly the invariant tyrosine where in all likelihood catalysis takes place
[1, 6]
.

References
Imported from IPR046341

1.Many paths to methyltransfer: a chronicle of convergence. Schubert HL, Blumenthal RM, Cheng X. Trends Biochem. Sci. 28, 329-35, (2003). View articlePMID: 12826405

2.The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin-mediated gene expression. Huang S, Shao G, Liu L. J. Biol. Chem. 273, 15933-9, (1998). View articlePMID: 9632640

3.Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Zhang X, Tamaru H, Khan SI, Horton JR, Keefe LJ, Selker EU, Cheng X. Cell 111, 117-27, (2002). View articlePMID: 12372305

4.Regulation of chromatin structure by site-specific histone H3 methyltransferases. Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T. Nature 406, 593-9, (2000). View articlePMID: 10949293

5.An archaeal SET domain protein exhibits distinct lysine methyltransferase activity towards DNA-associated protein MC1-alpha. Manzur KL, Zhou MM. FEBS Lett 579, 3859-65, (2005). PMID: 15978576

6.Structures of SET domain proteins: protein lysine methyltransferases make their mark. Yeates TO. Cell 111, 5-7, (2002). View articlePMID: 12372294

7.SET domain proteins modulate chromatin domains in eu- and heterochromatin. Jenuwein T, Laible G, Dorn R, Reuter G. Cell. Mol. Life Sci. 54, 80-93, (1998). View articlePMID: 9487389

8.Structure and catalytic mechanism of a SET domain protein methyltransferase. Trievel RC, Beach BM, Dirk LM, Houtz RL, Hurley JH. Cell 111, 91-103, (2002). View articlePMID: 12372303

9.PRDM1 decreases sensitivity of human NK cells to IL2-induced cell expansion by directly repressing CD25 (IL2RA). Akman B, Hu X, Liu X, Hatipoglu T, You H, Chan WC, Kucuk C. J Leukoc Biol 109, 901-914, (2021). PMID: 33145806

10.Crystal structure and functional analysis of the histone methyltransferase SET7/9. Wilson JR, Jing C, Walker PA, Martin SR, Howell SA, Blackburn GM, Gamblin SJ, Xiao B. Cell 111, 105-15, (2002). View articlePMID: 12372304

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