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
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 -