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Title: Structural basis for substrate recognition by the human N-terminal methyltransferase 1

α-N-terminal methylation represents a highly conserved and prevalent post-translational modification, yet its biological function has remained largely speculative. The recent discovery of α-N-terminal methyltransferase 1 (NTMT1) and its physiological substrates propels the elucidation of a general role of α-N-terminal methylation in mediating DNA-binding ability of the modified proteins. The phenotypes, observed from both NTMT1 knockdown in breast cancer cell lines and knockout mouse models, suggest the potential involvement of α-N-terminal methylation in DNA damage response and cancer development. In this study, we report the first crystal structures of human NTMT1 in complex with cofactor S-adenosyl-L-homocysteine (SAH) and six substrate peptides, respectively, and reveal that NTMT1 contains two characteristic structural elements (a β hairpin and an N-terminal extension) that contribute to its substrate specificity. Our complex structures, coupled with mutagenesis, binding, and enzymatic studies, also present the key elements involved in locking the consensus substrate motif XPK (X indicates any residue type other than D/E) into the catalytic pocket for α-N-terminal methylation and explain why NTMT1 prefers an XPK sequence motif. We propose a catalytic mechanism for α-N-terminal methylation. Overall, this study gives us the first glimpse of the molecular mechanism of α-N-terminal methylation and potentially contributes to the advent ofmore » therapeutic agents for human diseases associated with deregulated α-N-terminal methylation.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3]
  1. Univ. of Toronto, ON (Canada). Structural Genomics Consortium
  2. Virginia Commonwealth Univ., Richmond, VA (United States). Dept. of Medicinal Chemistry, Drug Discovery and Development. The Inst. for Structural Biology, Drug Discovery and Development
  3. Univ. of Toronto, ON (Canada). Structural Genomics Consortium. Dept. of Physiology
Publication Date:
OSTI Identifier:
1236265
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Genes and Development
Additional Journal Information:
Journal Volume: 29; Journal Issue: 22; Journal ID: ISSN 0890-9369
Publisher:
Cold Springs Harbor Press
Research Org:
Univ. of Toronto, ON (Canada); Virginia Commonwealth Univ., Richmond, VA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; α-N-terminal methylation; methyltransferase; NTMT1; crystal structure