PHD finger

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[edit] Introduction

The PHD finger (Plant Homeo Domain) was discovered in 1993 as a Cys₄-His-Cys₃ motif in the homeodomain protein HAT3 in Arabidopsis thaliana.

The PHD finger motif resembles the metal binding RING domain (Cys₃-His-Cys₄) and FYVE domain. It occurs as a single finger, but often in clusters of two or three, and it does also occur together with other domains, such as chromodomain and bromodomain.

The crystal structure of the PHD finger from human WSTF (Williams Syndrom Transcription Factor) shows that the conserved cysteines and histidine coordinate two Zn²⁺ ions. In general, the PHD finger adopts a globular fold, consisting of a two-stranded beta-sheet and an alpha-helix. The region consisting of these secondary structures and the residues involved in coordinating the Zn-ions are very conserved among species. The loop regions I and II are variable and could contribute functional specificity to the different PHD fingers.

The PHD finger, approximately 50-80 aminoacids in length, is found in more than 100 human proteins. Several of the proteins it occurs in are found in the nucleus, and are involved in chromatin-mediated gene regulation. There are now reports on several studies on the function of the PHD finger.

Recently PHD fingers in other proteins, including ING2, YNG1 and NURF, have been reported to bind to histone H3 tri-methylated on lysine 4 (H3K4me3), while other PHD fingers have tested negative in such assays. Interestingly, a protein called SMCX (or JARID1C) has a PHD finger, which has been reported to bind histone H3 tri-methylated lysine 9 (H3K9me3). Based on these recent publications, binding to tri-metylated lysines on histones may therefore be a property widespread among PHD fingers. Domains that bind to modified histones, we call epigenetic readers as they recognize the modification and binds to it.

H3K4me3 is associated with the transcription start site of active genes, while H3K9me3 is associated with inactive genes. There modifications of the histone lysines are dynamic, as there are methylases that add methyl groups to the lysines, and there are demethylases that remove methyl groups. The SMCX protein is actually a histone H3 lysine 4 demethylase, which means it is an enzyme that can remove the methyl groups of lysine 4 on histone 3 (making it H3K4me2 or H3K4me1). One can only speculate if the H3K9me3-binding of SMCX PHD domain provides a crosstalk between trimethylation of H3K9 and the demethylation of H3K4me3. Such crosstalks have been suggester earlier with other domains involved in chromatin regulation, and may provide a strictly coordinated regulation.

[edit] References

Schindler U, Beckmann H et al (1993) "HAT3-1, a novel Arabidopsis homeodomain protein containing a concerved cystein-rich region", Plant J, 4, 137-150
Aasland R, Gibson T, Stewart AF (2002) "The PHD finger: implications for chromatin-mediated transcriptional regulation", TIBS, 20, 56-59
Pascual J, Martinez-Yamout M et al (2000)," Structure of the PHD Zinc Finger from Human Williams-Beuren Syndrome Transcription Factor", Journal of Molecular Biology, 304, 723-729
Peña PV, Davrazou1 F, Shi X et al (2006),"Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2", Nature, 442, 100 - 103
Li H, Ilin S, Wang W et al (2006),"Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF", Nature, 442, 91-95
Iwase S, Lan F (2007),"The X-Linked Mental Retardation Gene SMCX/JARID1C Defines a Family of Histone H3 Lysine 4 Demethylases", Cell, 128, 1-12