PMID- 29253329 OWN - NLM STAT- MEDLINE DCOM- 20180522 LR - 20201209 IS - 1520-4995 (Electronic) IS - 0006-2960 (Print) IS - 0006-2960 (Linking) VI - 57 IP - 5 DP - 2018 Feb 6 TI - Characteristics of a PHD Finger Subtype. PG - 525-539 LID - 10.1021/acs.biochem.7b00705 [doi] AB - Although the plant homeodomain (PHD) finger superfamily is known for its site-specific readouts of histone tails, the origins of the mechanistic differences in histone H3 readout by different PHD subtypes remain less clear. We show that sequences containing the xCDxCDx motif in the PHD treble clef (xCDxCDx-PHD) constitute a distinct subtype, based on the following observations: (i) the amino acid composition of the binding site is strikingly different from other subtypes due to position-specific enrichment of negatively charged and bulky nonpolar residues, (ii) the binding site positions are mutually and positively correlated, and this correlation is absent in other subtypes, and (iii) there are only small structural deviations, despite low sequence similarity. The xCDxCDx-PHD constitutes approximately 20% of the PHD family, and the double PHD fingers (DPFs) are 10% of the total number of xCDxCDx-PHDs. This subtype originated early in the evolution of eukaryotes but has diversified within the metazoan lineage. Despite sequence diversification, the positions of the enriched nonpolar residues, in particular, show very small structural deviations, suggesting critical contributions of nonpolar residues in the binding mechanism of this subtype. Using mutagenesis, we probed the contributions of the binding-site positions enriched in nonpolar residues in four xCDxCDx-PHD proteins and found that they contribute to the tight packing of the H3 residues. This effect may potentially be exploited, as we observed affinity enhancement upon substituting a bulky nonpolar residue at the same binding site in another histone reader. Overall, we present a detailed characterization of PHD subtypes. FAU - Boamah, Daniel AU - Boamah D AD - Chemistry & Biochemistry, South Dakota State University , Brookings, South Dakota 57007, United States. FAU - Lin, Tao AU - Lin T AD - Chemistry & Biochemistry, South Dakota State University , Brookings, South Dakota 57007, United States. FAU - Poppinga, Franchesca A AU - Poppinga FA AD - Chemistry & Biochemistry, South Dakota State University , Brookings, South Dakota 57007, United States. FAU - Basu, Shraddha AU - Basu S AD - Chemistry & Biochemistry, South Dakota State University , Brookings, South Dakota 57007, United States. FAU - Rahman, Shahariar AU - Rahman S AD - Chemistry & Biochemistry, South Dakota State University , Brookings, South Dakota 57007, United States. FAU - Essel, Francisca AU - Essel F AD - Chemistry & Biochemistry, South Dakota State University , Brookings, South Dakota 57007, United States. FAU - Chakravarty, Suvobrata AU - Chakravarty S AUID- ORCID: 0000-0002-0044-3931 AD - Chemistry & Biochemistry, South Dakota State University , Brookings, South Dakota 57007, United States. AD - BioSNTR, Brookings, South Dakota 57007, United States. LA - eng GR - R15 GM116040/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180105 PL - United States TA - Biochemistry JT - Biochemistry JID - 0370623 RN - 0 (CCAAT-Enhancer-Binding Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (DPF3 protein, human) RN - 0 (Histones) RN - 0 (Transcription Factors) RN - EC 2.3.1.48 (Histone Acetyltransferases) RN - EC 2.3.1.48 (KAT6A protein, human) RN - EC 2.3.2.27 (UHRF1 protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - Binding Sites MH - CCAAT-Enhancer-Binding Proteins/chemistry/metabolism MH - DNA-Binding Proteins/chemistry/metabolism MH - Histone Acetyltransferases/chemistry/metabolism MH - Histones/chemistry/metabolism MH - Humans MH - Models, Molecular MH - *PHD Zinc Fingers MH - Protein Binding MH - Transcription Factors/chemistry/metabolism MH - Ubiquitin-Protein Ligases PMC - PMC6048597 MID - NIHMS978760 COIS- The authors declare no competing financial interest. EDAT- 2017/12/19 06:00 MHDA- 2018/05/23 06:00 PMCR- 2019/02/06 CRDT- 2017/12/19 06:00 PHST- 2017/12/19 06:00 [pubmed] PHST- 2018/05/23 06:00 [medline] PHST- 2017/12/19 06:00 [entrez] PHST- 2019/02/06 00:00 [pmc-release] AID - 10.1021/acs.biochem.7b00705 [doi] PST - ppublish SO - Biochemistry. 2018 Feb 6;57(5):525-539. doi: 10.1021/acs.biochem.7b00705. Epub 2018 Jan 5.