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evolution
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METTL11a, i.e. NRMT, encodes a 25 kDa protein in the methyltransferase 11 family, most members of which methylate metabolites or other small molecules. alpha-N-methyltransferase is a conserved member of a superfamily of non-SET domain enzymes
evolution
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Rkm2 belongs to the SET domain methyltransferases
evolution
enzymatic functional conservation of NRMT1 across species, evolutionary conservation of histone alpha-N-modification. Coevolution of NRMT1 recognition motifs in RCC1, CENP-A, and CENP-B, in which sequences 1SPKRIA6 of RCC1, 1GPRRRS6 of CENP-A, and 1GPKRRQ6 of CENP-B co-occur in mammals but are all missing in lower organisms. In contrast, the NRMT1 recognition motif of histone H2B is conserved from ciliates to insects but is lost in mammals. Remarkably, yeast and chicken orthologues of the above proteins do not harbor an NRMT1 recognition motif, suggesting that NRMT1 may exert its cellular function in these organisms through other protein substrates
evolution
enzyme Efm5 is a distinct type of eukaryotic N-terminal methyltransferase as, unlike the three other known eukaryotic N-terminal methyltransferases, its substrate does not have an N-terminal [A/P/S]-P-K motif. The N-terminal methylation of eEF1A is also present in human catalyzed by enzyme N6AMT2, this conservation over a large evolutionary distance suggests it to be of functional importance. The trimethylation of Lys79 in eEF1A is conserved from yeast to human. Human enzyme N6AMT2 is the direct orthologue of the yeast Efm5, and Efm5 and N6AMT2 can methylate eEF1A from either species in vitro
evolution
structural comparison of isozymes NTMT1 and NTMT2 (EC 2.1.1.299), overview. NTMT1 and NTMT2 employ a similar substrate recognition mode
evolution
the enzyme belongs to the methyltransferase like (METTL) family of class I methyltransferases containing seven-beta-strand methyltransferase motifs and Rossman folds for binding SAM. The N-terminal methyltransferase homologs NRMT1 (N-terminal RCC1 methyltransferase 1) and NRMT2 (N-terminal RCC1 methyltransferase 2), which following cleavage of the initiating methionine, methylate the alpha-amine of the first N-terminal residue of their substrates. NRMT1 and NRMT2 are 50% identical and 75% similar and share an N-terminal X-P-K consensus sequence. Although structurally similar, they differ in their catalytic activities
evolution
the enzyme is a distinct type of eukaryotic N-terminal methyltransferase as, unlike the three other known eukaryotic N-terminal methyltransferases, its substrate does not have an N-terminal [A/P/S]-P-K motif. The N-terminal methylation of eEF1A is also present in yeast catalyzed by enzymes Efm5 and Efm7, this conservation over a large evolutionary distance suggests it to be of functional importance. The trimethylation of Lys79 in eEF1A is conserved from yeast to human. Human enzyme N6AMT2 is the direct orthologue of the yeast Efm5, and Efm5 and N6AMT2 can methylate eEF1A from either species in vitro. Methyltransferases that act on lysine 79 in eEF1A are conserved from yeast to human
evolution
YLR285W is termed elongation factor methyltransferase 7 (Efm7). This enzyme is a distinct type of eukaryotic N-terminal methyltransferase as, unlike the three other known eukaryotic N-terminal methyltransferases, its substrate does not have an N-terminal [A/P/S]-P-K motif. The N-terminal methylation of eEF1A is also present in human catalyzed by enzyme N6AMT2, this conservation over a large evolutionary distance suggests it to be of functional importance. The trimethylation of Lys79 in eEF1A is conserved from yeast to human
evolution
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Rkm2 belongs to the SET domain methyltransferases
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evolution
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enzyme Efm5 is a distinct type of eukaryotic N-terminal methyltransferase as, unlike the three other known eukaryotic N-terminal methyltransferases, its substrate does not have an N-terminal [A/P/S]-P-K motif. The N-terminal methylation of eEF1A is also present in human catalyzed by enzyme N6AMT2, this conservation over a large evolutionary distance suggests it to be of functional importance. The trimethylation of Lys79 in eEF1A is conserved from yeast to human. Human enzyme N6AMT2 is the direct orthologue of the yeast Efm5, and Efm5 and N6AMT2 can methylate eEF1A from either species in vitro
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evolution
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YLR285W is termed elongation factor methyltransferase 7 (Efm7). This enzyme is a distinct type of eukaryotic N-terminal methyltransferase as, unlike the three other known eukaryotic N-terminal methyltransferases, its substrate does not have an N-terminal [A/P/S]-P-K motif. The N-terminal methylation of eEF1A is also present in human catalyzed by enzyme N6AMT2, this conservation over a large evolutionary distance suggests it to be of functional importance. The trimethylation of Lys79 in eEF1A is conserved from yeast to human
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malfunction
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loss of the Saccharomyces cerevisiae ORF YBR261c/TAE results in the loss of the N-terminal methylation of both Rpl12ab and Rps25a/Rps25b
malfunction
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methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects, and non-methylatable mutants of RCC1 are defective in chromatin association, and their expression in a wild-type background produces supernumerary spindle poles and missegregation of mitotic chromosomes, most likely due to the disruption of the Ran gradient
malfunction
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loss of the N-terminal methyltransferase NRMT1 increases sensitivity to DNA damage and promotes mammary oncogenesis. Enzyme NRMT1 knockdown significantly enhances the sensitivity of breast cancer cell lines to both etoposide treatment and gamma-irradiation, as well as, increases proliferation rate, invasive potential, anchorage-independent growth, xenograft tumor size, and tamoxifen sensitivity, e.g. in MCF-7 cells. NRMT1 knockdown promotes growth of excision repair positive breast cancer cell lines, but has no effect on the normally low NRMT1-expressing SKBR-3 and MDA-MB-231 cells. Phenotype, overview
malfunction
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NTMT1 is upregulated in a variety of cancers and knockdown of NTMT1 results in cell mitotic defects
malfunction
aberrant N-terminal methylation has been implicated in several cancers and developmental diseases
malfunction
deletion of YBR261C in yeast abolishes N-terminal methylation, which consequently alters the ribosomal profile and leads to defects in both translational efficiency and fidelity. Overexpression of YBR261 validates its involvement in protein synthesis
malfunction
deletion of YLR285W results in the loss of N-terminal and lysine methylation in vivo, whereas overexpression of YLR285W results in an increase of methylation at these sites
malfunction
in vivo, complete knockout of NRMT1 via homologous recombination or CRISPR/Cas9 abolishes N-terminal trimethylation
malfunction
knockdown of NTMT1 results in hypersensitivity of breast cancer cell lines to doublestranded DNA breaks (DSBs) and increased proliferation of estrogen receptor positive breast cancer cells MCF-7 and LCC9
malfunction
knockdown of NTMT1 results in mitotic defects and sensitizes etoposide and gamma irradiation in breast cancer cell lines such as MCF-7 and LCC9
malfunction
loss of eEF1A trimethylation at Lys79 upon knockout of YGR001C
malfunction
mutation and deletion of PrmA causes no growth defects or any distinct phenotype in Escherichia coli
malfunction
mutation and deletion of PrmA causes no growth defects or any distinct phenotype in Thermus thermophilus
malfunction
the activity of the D577A mutant decreases the enzymatic activity by about half
malfunction
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mutation and deletion of PrmA causes no growth defects or any distinct phenotype in Thermus thermophilus
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malfunction
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deletion of YBR261C in yeast abolishes N-terminal methylation, which consequently alters the ribosomal profile and leads to defects in both translational efficiency and fidelity. Overexpression of YBR261 validates its involvement in protein synthesis
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malfunction
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loss of eEF1A trimethylation at Lys79 upon knockout of YGR001C
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malfunction
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deletion of YLR285W results in the loss of N-terminal and lysine methylation in vivo, whereas overexpression of YLR285W results in an increase of methylation at these sites
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malfunction
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mutation and deletion of PrmA causes no growth defects or any distinct phenotype in Thermus thermophilus
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metabolism
protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. Functions of methylated glycine, alanine, and serine, overview
metabolism
protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. Functions of methylated glycine, alanine, and serine, overview
metabolism
protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. Functions of methylated glycine, alanine, and serine, overview
metabolism
protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. The alpha-N-terminal methylation has been reported on various N-terminal sequences in prokaryotic proteins. Functions of methylated glycine, alanine, and serine, overview
metabolism
protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. The alpha-N-terminal methylation has been reported on various N-terminal sequences in prokaryotic proteins. Functions of methylated glycine, alanine, and serine, overview
metabolism
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protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. The alpha-N-terminal methylation has been reported on various N-terminal sequences in prokaryotic proteins. Functions of methylated glycine, alanine, and serine, overview
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metabolism
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protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. Functions of methylated glycine, alanine, and serine, overview
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metabolism
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protein alpha-N-terminal methylation is catalyzed by prokaryotic and eukaryotic protein N-terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein-protein interactions. The alpha-N-terminal methylation has been reported on various N-terminal sequences in prokaryotic proteins. Functions of methylated glycine, alanine, and serine, overview
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physiological function
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importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation. Function of the alpha-N-methylation is not solely to stabilize chromatin associations, but may have a more general role in the regulation of electrostatic interactions
physiological function
protein X-Pro-Lys N-terminal methylation reactions catalyzed by the enzyme may be widespread in nature
physiological function
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the N-terminal protein methyltransferase catalyzes the modification of two ribosomal protein substrates, Rpl12ab and Rps25a/Rps25b, the YBR261C/TAE1 product is necessary for the formation of the dimethylproline residue in each of these ribosomal proteins. Protein X-Pro-Lys N-terminal methylation reactions catalyzed by the enzyme may be widespread in nature
physiological function
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alpha-N-terminal methylation seems to regulate protein stability via N-end rule pathways or mediate proteinprotein interactions. The enzyme also mediates protein-DNA interactions between chromatin and regulator of chromatin condensation
physiological function
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enzyme NRMT1 acts as a tumor suppressor protein involved in multiple DNA repair pathways, role of N-terminal methylation in DNA repair. N-terminal methylation of DDB2 by NRMT1 is necessary for its recruitment to UV-induced DNA damage and proper execution of nucleotide excision repai. Additional NRMT1 targets, BRCA1 associated protein 1 (BAP1) and poly-ADP-ribosylase 3 (PARP3), are involved in DNA double strand break repair. BAP1 is a deubiquitinating enzyme recruited to DNA and required for appropriate assembly of homologous recombination factors during DSB. PARP3 poly-ADP-ribosylates proteins at DSBs and promotes NHEJ
physiological function
biological significances of NTMT1 in cell mitosis, chromatin segregation, and damaged DNA repair, along with its implications in cancer and aging
physiological function
dNTMT is mainly located in the nucleus, where the majority of chromatin-bound H2B is methylated. dNTMT recognizes the N-terminal sequence of Drosophila melanogaster H2B (PPKTSG), which conforms to the canonical X-P-K recognition motif for its mammalian orthologues (X=A, P, or S). dNTMT methylation is not processive since monomethylated Pro is accumulated during the methylation reaction. In addition, dART8, a PRMT for H3R2 methylation, negatively regulated H2B N-terminal methylation, thus suggesting crosstalk between methylation on two histone tails
physiological function
eukaryotic elongation factor 1A (eEF1A) is an essential, highly methylated protein that facilitates translational elongation by delivering aminoacyl-tRNAs to ribosomes. Eukaryotic protein N-terminal methyltransferase from Saccharomyces cerevisiae, YLR285W, methylates eEF1A at a previously undescribed high-stoichiometry N-terminal site and at the adjacent lysine
physiological function
METTL13/FEAT is implicated in tumorigenesis in vivo by suppressing apoptosis. METTL13/FEAT protein is also implied as a tumor suppressor in bladder carcinoma by negatively regulating cell proliferation, migration, and invasion in bladder cancer cells
physiological function
N-terminal methylation is a regulator of protein-DNA and protein-protein interactions for a number of proteins, such as RCC1, CENPA/B, DDB2, PARP3, an MYL9, playing important roles in cell mitotic progression, DNA damage repair, and regulation of protein function. N-terminal methyltransferase 1 (NTMT1) catalyzes the N-terminal methylation of proteins with a specific N-terminal motif after methionine removal. Obg-like ATPase 1 (OLA1) protein, a protein involved in many critical cellular functions, is methylated in vivo by NTMT1, NTMT1 is responsible for OLA1 methylation in vivo
physiological function
NRMT1 is a ubiquitously expressed distributive trimethylase
physiological function
NRMT1 is an N-terminal methyltransferase that methylates histone CENP-A as well as nonhistone substrates
physiological function
PrmA preferentially methylates free ribosomal protein L11 over an assembled 50S ribosomal subunit
physiological function
PrmA preferentially methylates free ribosomal protein L11 over an assembled 50S ribosomal subunit
physiological function
protein lysine/arginine methylation, the addition of a methyl group at the free alpha-N-termini of proteins represents a unique mode of post-translational modification. NTMT1 is an S-adenosyl-L-methionine (SAM)-dependent methyltransferase. During the enzymatic reaction, NTMT1 transfers a methyl group from SAM to the alpha-amino group of the protein substrates, resulting in the production of S-adenosyl-L-homocysteine (SAH) and alpha-N-methylated proteins. NTMT1 recognizes proteins bearing an N-terminal X-P-K/R consensus sequence, including RCC1, RB1, DDB2, CENP-A/B, PARP3, etc.
physiological function
protein N-terminal methyltransferase 1 (NTMT1) plays an important role in regulating mitosis and DNA repair
physiological function
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PrmA preferentially methylates free ribosomal protein L11 over an assembled 50S ribosomal subunit
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physiological function
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eukaryotic elongation factor 1A (eEF1A) is an essential, highly methylated protein that facilitates translational elongation by delivering aminoacyl-tRNAs to ribosomes. Eukaryotic protein N-terminal methyltransferase from Saccharomyces cerevisiae, YLR285W, methylates eEF1A at a previously undescribed high-stoichiometry N-terminal site and at the adjacent lysine
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physiological function
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PrmA preferentially methylates free ribosomal protein L11 over an assembled 50S ribosomal subunit
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additional information
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both full-length and truncated forms of the enzyme catalyze methylation of the alpha-amine of the N-terminal methionine of the small subunit of Rubisco
additional information
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the enzyme contains two characteristic structural elements, a beta hairpin and an N-terminal extension, that contribute to its substrate specificity. Identification of key elements involved in locking the consensus substrate motif XPK (X indicates any residue type other than D/E) into the catalytic pocket for alpha-N-terminal methylation, NTMT1 prefers an XPK sequence motif, catalytic mechanism for alpha-N-terminal methylation and overall structure of the NTMT1 ternary complexes, verview
additional information
analysis of crystal structures of NRMT1 and NRMT2 (PDB IDs 2EX4 and 5UBB, determined to 1.75 and 2.0 A, respectively), homology modeling. Modeling of NRMT1 and NRMT2 heterotrimer, interaction analysis, overview
additional information
substrate and ligand binding structures of NTMT1 and NTMT2 (EC 2.1.1.299), overview
additional information
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substrate and ligand binding structures of NTMT1 and NTMT2 (EC 2.1.1.299), overview
additional information
substrate recognition and catalytic mechanisms, overview
additional information
substrate recognition and catalytic mechanisms, overview
additional information
substrate recognition and catalytic mechanisms, overview
additional information
substrate recognition and catalytic mechanisms, overview
additional information
substrate recognition and catalytic mechanisms, overview. Conformational changes are necessary for the recognition of multiple substrate sites
additional information
substrate recognition and catalytic mechanisms, overview. Efm7 substrate recognition may require the three-dimensional structure, which is different from the classic linear X-P-K/R motif recognition by other eukaryotic protein NTMTs
additional information
substrate recognition and catalytic mechanisms, overview. Efm7 substrate recognition may require the three-dimensional structure, which is different from the classic linear X-P-K/R motif recognition by other eukaryotic protein NTMTs
additional information
substrate recognition and catalytic mechanisms, overview. Ligand binding structures are analyzed. NTMT1-catalyzed methylation follows a random sequential Bi Bi mechanism, which involves the formation of a ternary complex with either substrate binding to NTMT1 first. Two highly conserved Asp180 and His140 act as general bases to facilitate deprotonation of the alpha-amino group of the N-terminus to attack SAM to transfer the methyl group
additional information
substrate recognition and catalytic mechanisms, overview. Ligand binding structures are analyzed. NTMT1-catalyzed methylation follows a random sequential Bi Bi mechanism, which involves the formation of a ternary complex with either substrate binding to NTMT1 first. Two highly conserved Asp180 and His140 act as general bases to facilitate deprotonation of the alpha-amino group of the N-terminus to attack SAM to transfer the methyl group
additional information
substrate recognition and catalytic mechanisms, overview. METTL13 has two distinct MTase domains: N- and C-terminal domains that appear to have different recognition preferences. The C-terminal domain of dual MTase METTL13 is responsible for the a-N-terminal methylation of eEF1A. The unique interaction of Asp577 with the alpha-amino group of Gly1 is required for enzymatic activity
additional information
substrate recognition and catalytic mechanisms, overview. METTL13 has two distinct MTase domains: N- and C-terminal domains that appear to have different recognition preferences. The C-terminal domain of dual MTase METTL13 is responsible for the a-N-terminal methylation of eEF1A. The unique interaction of Asp577 with the alpha-amino group of Gly1 is required for enzymatic activity
additional information
ternary structures of human NRMT1 bound to alpha-N-methylated peptides of human histone CENP-A or fruit fly histone H2B in the presence of SAH, NRMT1 adopts a core methyltransferase fold that resembles DOT1L and PRMT but not SET domain family histone methyltransferases, key substrate recognition and catalytic residues, NTMT1 structure-function analysis, overview. NRMT1 harbors a canonical SAM-dependent methyltransferase (SAM-MTase) core fold consisting of a seven-stranded beta-sheet (beta1-beta7) sandwiched by five flanking alpha-helices. Active site structure and catalytic mechanism analysis
additional information
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ternary structures of human NRMT1 bound to alpha-N-methylated peptides of human histone CENP-A or fruit fly histone H2B in the presence of SAH, NRMT1 adopts a core methyltransferase fold that resembles DOT1L and PRMT but not SET domain family histone methyltransferases, key substrate recognition and catalytic residues, NTMT1 structure-function analysis, overview. NRMT1 harbors a canonical SAM-dependent methyltransferase (SAM-MTase) core fold consisting of a seven-stranded beta-sheet (beta1-beta7) sandwiched by five flanking alpha-helices. Active site structure and catalytic mechanism analysis
additional information
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substrate recognition and catalytic mechanisms, overview
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additional information
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substrate recognition and catalytic mechanisms, overview
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additional information
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substrate recognition and catalytic mechanisms, overview. Efm7 substrate recognition may require the three-dimensional structure, which is different from the classic linear X-P-K/R motif recognition by other eukaryotic protein NTMTs
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additional information
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substrate recognition and catalytic mechanisms, overview
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