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Title: Structural and Functional Profiling of the Human Histone Methyltransferase SMYD3

Abstract

The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain SET histone methyltransferases that are implicated in human cancer progression. Here we report an analysis of the crystal structure of the full length human SMYD3 in a complex with an analog of the S-adenosyl methionine (SAM) methyl donor cofactor. The structure revealed an overall compact architecture in which the 'split-SET' domain adopts a canonical SET domain fold and closely assembles with a Zn-binding MYND domain and a C-terminal superhelical 9 ?-helical bundle similar to that observed for the mouse SMYD1 structure. Together, these structurally interlocked domains impose a highly confined binding pocket for histone substrates, suggesting a regulated mechanism for its enzymatic activity. Our mutational and biochemical analyses confirm regulatory roles of the unique structural elements both inside and outside the core SET domain and establish a previously undetected preference for trimethylation of H4K20.

Authors:
; ; ; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2];  [2];  [2]
  1. (AltheaDx)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERNIH
OSTI Identifier:
1050077
Resource Type:
Journal Article
Journal Name:
PLoS One
Additional Journal Information:
Journal Volume: 6; Journal Issue: (7) ; 07, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; FUNCTIONALS; HISTONES; METHIONINE; NEOPLASMS; PROTEINS; SUBSTRATES

Citation Formats

Foreman, Kenneth W., Brown, Mark, Park, Frances, Emtage, Spencer, Harriss, June, Das, Chhaya, Zhu, Li, Crew, Andy, Arnold, Lee, Shaaban, Salam, Tucker, Philip, DiscoverEluc.), Abbott Bioresearch), OSI Pharm.), Lilly), and Texas). Structural and Functional Profiling of the Human Histone Methyltransferase SMYD3. United States: N. p., 2012. Web. doi:10.1371/journal.pone.0022290.
Foreman, Kenneth W., Brown, Mark, Park, Frances, Emtage, Spencer, Harriss, June, Das, Chhaya, Zhu, Li, Crew, Andy, Arnold, Lee, Shaaban, Salam, Tucker, Philip, DiscoverEluc.), Abbott Bioresearch), OSI Pharm.), Lilly), & Texas). Structural and Functional Profiling of the Human Histone Methyltransferase SMYD3. United States. doi:10.1371/journal.pone.0022290.
Foreman, Kenneth W., Brown, Mark, Park, Frances, Emtage, Spencer, Harriss, June, Das, Chhaya, Zhu, Li, Crew, Andy, Arnold, Lee, Shaaban, Salam, Tucker, Philip, DiscoverEluc.), Abbott Bioresearch), OSI Pharm.), Lilly), and Texas). Tue . "Structural and Functional Profiling of the Human Histone Methyltransferase SMYD3". United States. doi:10.1371/journal.pone.0022290.
@article{osti_1050077,
title = {Structural and Functional Profiling of the Human Histone Methyltransferase SMYD3},
author = {Foreman, Kenneth W. and Brown, Mark and Park, Frances and Emtage, Spencer and Harriss, June and Das, Chhaya and Zhu, Li and Crew, Andy and Arnold, Lee and Shaaban, Salam and Tucker, Philip and DiscoverEluc.) and Abbott Bioresearch) and OSI Pharm.) and Lilly) and Texas)},
abstractNote = {The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain SET histone methyltransferases that are implicated in human cancer progression. Here we report an analysis of the crystal structure of the full length human SMYD3 in a complex with an analog of the S-adenosyl methionine (SAM) methyl donor cofactor. The structure revealed an overall compact architecture in which the 'split-SET' domain adopts a canonical SET domain fold and closely assembles with a Zn-binding MYND domain and a C-terminal superhelical 9 ?-helical bundle similar to that observed for the mouse SMYD1 structure. Together, these structurally interlocked domains impose a highly confined binding pocket for histone substrates, suggesting a regulated mechanism for its enzymatic activity. Our mutational and biochemical analyses confirm regulatory roles of the unique structural elements both inside and outside the core SET domain and establish a previously undetected preference for trimethylation of H4K20.},
doi = {10.1371/journal.pone.0022290},
journal = {PLoS One},
number = (7) ; 07, 2011,
volume = 6,
place = {United States},
year = {2012},
month = {10}
}