Structure and Site-Specific Recognition of Histone H3 by the PHD Finger of Human Autoimmune Regulator

Suvobrata Chakravarty; Lei Zeng; Ming Ming Zhou

doi:10.1016/j.str.2009.02.017

Structure and Site-Specific Recognition of Histone H3 by the PHD Finger of Human Autoimmune Regulator

Suvobrata Chakravarty, Lei Zeng, Ming Ming Zhou

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

Abstract

Human autoimmune regulator (AIRE) functions to control thymic expression of tissue-specific antigens via sequence-specific histone H3 recognition by its plant homeodomain (PHD) finger. Mutations in the AIRE PHD finger have been linked to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide. The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3, and particularly key electrostatic interactions of a conserved aspartic acid 297 in AIRE with the unmodified lysine 4 of histone H3 (H3K4). NMR binding study with H3 peptides carrying known posttranslational modifications flanking H3K4 confirms that transcriptional regulation by AIRE through its interactions with histone H3 is confined to the first N-terminal eight residues in H3. Our study offers a molecular explanation for the APECED mutations and helps define a subclass of the PHD finger family proteins that recognize histone H3 in a sequence-specific manner.

Original language	English
Pages (from-to)	670-679
Number of pages	10
Journal	Structure
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.str.2009.02.017
State	Published - 13 May 2009
Externally published	Yes

Keywords

DNA
PROTEIN

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title = "Structure and Site-Specific Recognition of Histone H3 by the PHD Finger of Human Autoimmune Regulator",

abstract = "Human autoimmune regulator (AIRE) functions to control thymic expression of tissue-specific antigens via sequence-specific histone H3 recognition by its plant homeodomain (PHD) finger. Mutations in the AIRE PHD finger have been linked to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide. The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3, and particularly key electrostatic interactions of a conserved aspartic acid 297 in AIRE with the unmodified lysine 4 of histone H3 (H3K4). NMR binding study with H3 peptides carrying known posttranslational modifications flanking H3K4 confirms that transcriptional regulation by AIRE through its interactions with histone H3 is confined to the first N-terminal eight residues in H3. Our study offers a molecular explanation for the APECED mutations and helps define a subclass of the PHD finger family proteins that recognize histone H3 in a sequence-specific manner.",

keywords = "DNA, PROTEIN",

author = "Suvobrata Chakravarty and Lei Zeng and Zhou, {Ming Ming}",

note = "Funding Information: We thank A. Meloni of the Consiglio Nazionale delle Ricerche (CNR; Cagliari, Italy) and M.C. Rosatelli of the Universita degli Studi di Cagliari, Italy, for kindly providing the cDNA encoding the human protein. We acknowledge the use of the NMR facility at the New York Structural Biology Center for this study. We also thank Alexander Plotnikov for technical advice on protein preparation, and Rinku Jain for helpful discussion. M.-M.Z. was in part supported by funds from the Dr. Golden and Harold Lamport Chair, and grants from the National Institutes of Health (GM73207 and CA87658). ",

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AU - Chakravarty, Suvobrata

AU - Zeng, Lei

AU - Zhou, Ming Ming

N1 - Funding Information: We thank A. Meloni of the Consiglio Nazionale delle Ricerche (CNR; Cagliari, Italy) and M.C. Rosatelli of the Universita degli Studi di Cagliari, Italy, for kindly providing the cDNA encoding the human protein. We acknowledge the use of the NMR facility at the New York Structural Biology Center for this study. We also thank Alexander Plotnikov for technical advice on protein preparation, and Rinku Jain for helpful discussion. M.-M.Z. was in part supported by funds from the Dr. Golden and Harold Lamport Chair, and grants from the National Institutes of Health (GM73207 and CA87658).

PY - 2009/5/13

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N2 - Human autoimmune regulator (AIRE) functions to control thymic expression of tissue-specific antigens via sequence-specific histone H3 recognition by its plant homeodomain (PHD) finger. Mutations in the AIRE PHD finger have been linked to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide. The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3, and particularly key electrostatic interactions of a conserved aspartic acid 297 in AIRE with the unmodified lysine 4 of histone H3 (H3K4). NMR binding study with H3 peptides carrying known posttranslational modifications flanking H3K4 confirms that transcriptional regulation by AIRE through its interactions with histone H3 is confined to the first N-terminal eight residues in H3. Our study offers a molecular explanation for the APECED mutations and helps define a subclass of the PHD finger family proteins that recognize histone H3 in a sequence-specific manner.

AB - Human autoimmune regulator (AIRE) functions to control thymic expression of tissue-specific antigens via sequence-specific histone H3 recognition by its plant homeodomain (PHD) finger. Mutations in the AIRE PHD finger have been linked to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide. The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3, and particularly key electrostatic interactions of a conserved aspartic acid 297 in AIRE with the unmodified lysine 4 of histone H3 (H3K4). NMR binding study with H3 peptides carrying known posttranslational modifications flanking H3K4 confirms that transcriptional regulation by AIRE through its interactions with histone H3 is confined to the first N-terminal eight residues in H3. Our study offers a molecular explanation for the APECED mutations and helps define a subclass of the PHD finger family proteins that recognize histone H3 in a sequence-specific manner.

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Structure and Site-Specific Recognition of Histone H3 by the PHD Finger of Human Autoimmune Regulator

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Keywords

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