High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation
| Autor: | Mengjie Shen, Cyril Dian, Ernesto Cota, Carmela Giglione, Pierre Legrand, Frédéric Rivière, Edward W. Tate, Thierry Meinnel, Thomas Asensio, Inmaculada Pérez-Dorado, Markus Ritzefeld |
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| Přispěvatelé: | Cancer Research UK, Medicines for Malaria Venture, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Maturation des proteines, destinée cellulaire et thérapeutique (PROMTI), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Imperial College London, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), ARDoc program from Region Ile-de-France (17012695), ANR-10-BLAN-1611,PalMyProt,Approche fonctionnelle intégrée des protéomes S-Palmitoylés et N-Myristoylés chez Arabidopsis(2010), ANR-10-LABX-0040,SPS,Saclay Plant Sciences(2010), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010) |
| Rok vydání: | 2020 |
| Předmět: |
Proteomics
0301 basic medicine [SDV]Life Sciences [q-bio] Lysine General Physics and Astronomy Peptide Crystallography X-Ray 01 natural sciences Myristic Acid Protein Structure Secondary Substrate Specificity Acylation Protein structure Catalytic Domain Transferase lcsh:Science chemistry.chemical_classification Multidisciplinary Chemistry HYDROLYSIS 3. Good health Multidisciplinary Sciences TARGET Enzyme mechanisms Science & Technology - Other Topics lipids (amino acids peptides and proteins) Stereochemistry Science Glycine COA Article General Biochemistry Genetics and Molecular Biology Catalysis 03 medical and health sciences Structure-Activity Relationship MALARIA Transferases REVEALS Structure–activity relationship Humans Coenzyme A PRECURSOR X-ray crystallography Myristoylation Science & Technology 010405 organic chemistry General Chemistry 0104 chemical sciences ACYLATION Protein Structure Tertiary Kinetics 030104 developmental biology Acyltransferases BOUND MYRISTOYLCOA Mutation lcsh:Q INHIBITORS Chemical modification LEISHMANIASIS |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020) Nature Communications 'Nature Communications ', vol: 11, pages: 1132-1-1132-15 (2020) Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.1132. ⟨10.1038/s41467-020-14847-3⟩ Nature Communications, 2020, 11 (1), pp.1132. ⟨10.1038/s41467-020-14847-3⟩ |
| ISSN: | 2041-1723 |
| Popis: | The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). Here, we present high-resolution human NMT1 structures co-crystallised with reactive cognate lipid and peptide substrates, revealing high-resolution snapshots of the entire catalytic mechanism from the initial to final reaction states. Structural comparisons, together with biochemical analysis, provide unforeseen details about how NMT1 reaches a catalytically competent conformation in which the reactive groups are brought into close proximity to enable catalysis. We demonstrate that this mechanism further supports efficient and unprecedented myristoylation of an N-terminal lysine side chain, providing evidence that NMT acts both as N-terminal-lysine and glycine myristoyltransferase. N-terminal glycine myristoyl transferases (NMTs) catalyse the myristoylation of eukaryotic proteins. Here, the authors provide insights into the catalytic mechanism of NMTs by determining the crystal structures of human NMT1 in complex with reactive cognate lipid and peptide substrates and further show that NMT1 also catalyses the acylation of N-terminal lysines. |
| Databáze: | OpenAIRE |
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