Structural Basis for Lower Lysine Methylation State-Specific Readout by MBT Repeats of L3MBTL1 and an Engineered PHD Finger

Haitao Li; Wolfgang Fischle; Wooikoon Wang; Elizabeth M. Duncan; Lena Liang; Satoko Murakami-Ishibe; C. David Allis; Dinshaw J. Patel

doi:10.1016/j.molcel.2007.10.023

Structural Basis for Lower Lysine Methylation State-Specific Readout by MBT Repeats of L3MBTL1 and an Engineered PHD Finger

Haitao Li, Wolfgang Fischle, Wooikoon Wang, Elizabeth M. Duncan, Lena Liang, Satoko Murakami-Ishibe, C. David Allis, Dinshaw J. Patel

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

171 Scopus citations

Abstract

Human L3MBTL1, which contains three malignant brain tumor (MBT) repeats, binds monomethylated and dimethylated lysines, but not trimethylated lysines, in several histone sequence contexts. In crystal structures of L3MBTL1 complexes, the monomethyl- and dimethyllysines insert into a narrow and deep cavity of aromatic residue-lined pocket 2, while a proline ring inserts into shallower pocket 1. We have also engineered a single Y to E substitution within the aromatic cage of the BPTF PHD finger, resulting in a reversal of binding preference from trimethyl- to dimethyllysine in an H3K4 sequence context. In both the "cavity insertion" (L3MBTL1) and "surface groove" (PHD finger) modes of methyllysine recognition, a carboxylate group both hydrogen bonds and ion pairs to the methylammonium proton. Our structural and binding studies of these two modules provide insights into the molecular principles governing the decoding of lysine methylation states, thereby highlighting a methylation state-specific layer of histone mark readout impacting on epigenetic regulation.

Original language	English
Pages (from-to)	677-691
Number of pages	15
Journal	Molecular Cell
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2007.10.023
State	Published - Nov 30 2007

Bibliographical note

Funding Information:
D.J.P. is supported by funds from the Abby Rockefeller Mauze Trust and the Dewitt Wallace and Maloris Foundations, and C.D.A. is supported by an NIH MERIT award and funds from Rockefeller University. We thank Drs. Nagesh Kalakonda, Stephen D. Nimer, Alex Ruthenburg, Sean Taverna, Valentina Tereshko, and Joanna Wysocka for their helpful advice and comments. We thank the Peptide Core Facilities at Sloan-Kettering (S.S. Yi at Microchemistry and Proteomics) and Rockefeller University for the synthesis and purification of K4-methylated H3 peptides. We would like to thank the staff at beamline NE CAT 24ID-C of the Advanced Photon Source at the Argonne National Laboratory, supported by the US Department of Energy, for assistance with data collection.

Funding

D.J.P. is supported by funds from the Abby Rockefeller Mauze Trust and the Dewitt Wallace and Maloris Foundations, and C.D.A. is supported by an NIH MERIT award and funds from Rockefeller University. We thank Drs. Nagesh Kalakonda, Stephen D. Nimer, Alex Ruthenburg, Sean Taverna, Valentina Tereshko, and Joanna Wysocka for their helpful advice and comments. We thank the Peptide Core Facilities at Sloan-Kettering (S.S. Yi at Microchemistry and Proteomics) and Rockefeller University for the synthesis and purification of K4-methylated H3 peptides. We would like to thank the staff at beamline NE CAT 24ID-C of the Advanced Photon Source at the Argonne National Laboratory, supported by the US Department of Energy, for assistance with data collection.

Funders	Funder number
Abby Rockefeller Mauze Trust
Dewitt Wallace and Maloris Foundations
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	P30CA008748
Rockefeller University

Keywords

DNA

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2007.10.023

Cite this

@article{763e54047ae8419c86832dd2e388730a,

title = "Structural Basis for Lower Lysine Methylation State-Specific Readout by MBT Repeats of L3MBTL1 and an Engineered PHD Finger",

abstract = "Human L3MBTL1, which contains three malignant brain tumor (MBT) repeats, binds monomethylated and dimethylated lysines, but not trimethylated lysines, in several histone sequence contexts. In crystal structures of L3MBTL1 complexes, the monomethyl- and dimethyllysines insert into a narrow and deep cavity of aromatic residue-lined pocket 2, while a proline ring inserts into shallower pocket 1. We have also engineered a single Y to E substitution within the aromatic cage of the BPTF PHD finger, resulting in a reversal of binding preference from trimethyl- to dimethyllysine in an H3K4 sequence context. In both the {"}cavity insertion{"} (L3MBTL1) and {"}surface groove{"} (PHD finger) modes of methyllysine recognition, a carboxylate group both hydrogen bonds and ion pairs to the methylammonium proton. Our structural and binding studies of these two modules provide insights into the molecular principles governing the decoding of lysine methylation states, thereby highlighting a methylation state-specific layer of histone mark readout impacting on epigenetic regulation.",

keywords = "DNA",

author = "Haitao Li and Wolfgang Fischle and Wooikoon Wang and Duncan, {Elizabeth M.} and Lena Liang and Satoko Murakami-Ishibe and Allis, {C. David} and Patel, {Dinshaw J.}",

note = "Funding Information: D.J.P. is supported by funds from the Abby Rockefeller Mauze Trust and the Dewitt Wallace and Maloris Foundations, and C.D.A. is supported by an NIH MERIT award and funds from Rockefeller University. We thank Drs. Nagesh Kalakonda, Stephen D. Nimer, Alex Ruthenburg, Sean Taverna, Valentina Tereshko, and Joanna Wysocka for their helpful advice and comments. We thank the Peptide Core Facilities at Sloan-Kettering (S.S. Yi at Microchemistry and Proteomics) and Rockefeller University for the synthesis and purification of K4-methylated H3 peptides. We would like to thank the staff at beamline NE CAT 24ID-C of the Advanced Photon Source at the Argonne National Laboratory, supported by the US Department of Energy, for assistance with data collection. ",

year = "2007",

month = nov,

day = "30",

doi = "10.1016/j.molcel.2007.10.023",

language = "English",

volume = "28",

pages = "677--691",

number = "4",

}

TY - JOUR

T1 - Structural Basis for Lower Lysine Methylation State-Specific Readout by MBT Repeats of L3MBTL1 and an Engineered PHD Finger

AU - Li, Haitao

AU - Fischle, Wolfgang

AU - Wang, Wooikoon

AU - Duncan, Elizabeth M.

AU - Liang, Lena

AU - Murakami-Ishibe, Satoko

AU - Allis, C. David

AU - Patel, Dinshaw J.

N1 - Funding Information: D.J.P. is supported by funds from the Abby Rockefeller Mauze Trust and the Dewitt Wallace and Maloris Foundations, and C.D.A. is supported by an NIH MERIT award and funds from Rockefeller University. We thank Drs. Nagesh Kalakonda, Stephen D. Nimer, Alex Ruthenburg, Sean Taverna, Valentina Tereshko, and Joanna Wysocka for their helpful advice and comments. We thank the Peptide Core Facilities at Sloan-Kettering (S.S. Yi at Microchemistry and Proteomics) and Rockefeller University for the synthesis and purification of K4-methylated H3 peptides. We would like to thank the staff at beamline NE CAT 24ID-C of the Advanced Photon Source at the Argonne National Laboratory, supported by the US Department of Energy, for assistance with data collection.

PY - 2007/11/30

Y1 - 2007/11/30

N2 - Human L3MBTL1, which contains three malignant brain tumor (MBT) repeats, binds monomethylated and dimethylated lysines, but not trimethylated lysines, in several histone sequence contexts. In crystal structures of L3MBTL1 complexes, the monomethyl- and dimethyllysines insert into a narrow and deep cavity of aromatic residue-lined pocket 2, while a proline ring inserts into shallower pocket 1. We have also engineered a single Y to E substitution within the aromatic cage of the BPTF PHD finger, resulting in a reversal of binding preference from trimethyl- to dimethyllysine in an H3K4 sequence context. In both the "cavity insertion" (L3MBTL1) and "surface groove" (PHD finger) modes of methyllysine recognition, a carboxylate group both hydrogen bonds and ion pairs to the methylammonium proton. Our structural and binding studies of these two modules provide insights into the molecular principles governing the decoding of lysine methylation states, thereby highlighting a methylation state-specific layer of histone mark readout impacting on epigenetic regulation.

AB - Human L3MBTL1, which contains three malignant brain tumor (MBT) repeats, binds monomethylated and dimethylated lysines, but not trimethylated lysines, in several histone sequence contexts. In crystal structures of L3MBTL1 complexes, the monomethyl- and dimethyllysines insert into a narrow and deep cavity of aromatic residue-lined pocket 2, while a proline ring inserts into shallower pocket 1. We have also engineered a single Y to E substitution within the aromatic cage of the BPTF PHD finger, resulting in a reversal of binding preference from trimethyl- to dimethyllysine in an H3K4 sequence context. In both the "cavity insertion" (L3MBTL1) and "surface groove" (PHD finger) modes of methyllysine recognition, a carboxylate group both hydrogen bonds and ion pairs to the methylammonium proton. Our structural and binding studies of these two modules provide insights into the molecular principles governing the decoding of lysine methylation states, thereby highlighting a methylation state-specific layer of histone mark readout impacting on epigenetic regulation.

KW - DNA

UR - http://www.scopus.com/inward/record.url?scp=36249026356&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36249026356&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2007.10.023

DO - 10.1016/j.molcel.2007.10.023

M3 - Article

C2 - 18042461

AN - SCOPUS:36249026356

SN - 1097-2765

VL - 28

SP - 677

EP - 691

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

Structural Basis for Lower Lysine Methylation State-Specific Readout by MBT Repeats of L3MBTL1 and an Engineered PHD Finger

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this