Molecular basis for histidine N1 position-specific methylation by CARNMT1

Cao, Ruili; Zhang, Xingrun; Liu, Xiaohui; Li, Yuanyuan; Li, Haitao

doi:10.1038/s41422-018-0003-0

Cited by 21 publications

(22 citation statements)

References 10 publications

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“…This enzyme catalyzes N 1 -methylation of the histidine imidazole ring of carnosine (β-alanyl-L-histidine), an abundant dipeptide in the skeletal muscle of vertebrates. Recently, the structures of CARNMT1 bound to analogs of N 1 -methylhistidine were also reported (Cao et al, 2018), allowing us to compare N 3 -histidine methylation by SETD3 with N 1 -histidine methylation by CARNMT1 by studying the two complexes (Figure 2A and E). We found that SETD3 and CARNMT1 not only adopt different folds and AdoHcy-binding modes, but also display distinct histidine recognition and catalysis mechanisms.…”

Section: Discussionmentioning

confidence: 97%

“…We found that SETD3 and CARNMT1 not only adopt different folds and AdoHcy-binding modes, but also display distinct histidine recognition and catalysis mechanisms. Asp316 of CARNMT1 forms two hydrogen bonds with the imidazole ring of the histidine to facilitate its deprotonation (Figure 2E) (Cao et al, 2018). In the SETD3–substrate complex, His73 stacks with Tyr313 and is hydrogen-bonded to the main chain carbonyl group of Asp275 (Figure 2A), which orients the His73 imidazole ring for efficient catalysis.…”

Section: Discussionmentioning

confidence: 99%

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Structural insights into SETD3-mediated histidine methylation on β-actin

Guo

Liao

Kwiatkowski

et al. 2019

eLife

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SETD3 is a member of the SET (Su(var)3–9, Enhancer of zeste, and Trithorax) domain protein superfamily and plays important roles in hypoxic pulmonary hypertension, muscle differentiation, and carcinogenesis. Previously, we identified SETD3 as the actin-specific methyltransferase that methylates the N3 of His73 on β-actin (Kwiatkowski et al., 2018). Here, we present two structures of S-adenosyl-L-homocysteine-bound SETD3 in complex with either an unmodified β-actin peptide or its His-methylated variant. Structural analyses, supported by biochemical experiments and enzyme activity assays, indicate that the recognition and methylation of β-actin by SETD3 are highly sequence specific, and that both SETD3 and β-actin adopt pronounced conformational changes upon binding to each other. In conclusion, this study is the first to show a catalytic mechanism of SETD3-mediated histidine methylation on β-actin, which not only throws light on the protein histidine methylation phenomenon but also facilitates the design of small molecule inhibitors of SETD3.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Structural insights into SETD3-mediated histidine methylation on β-actin

Guo

Liao

Kwiatkowski

et al. 2019

eLife

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“…Remarkably, histidine methylation could occur to N1 or N3 position of its imidazole ring, posing an interesting topic to understand the biology underlying position-specific methylation of histidine. Previously, we have revealed the structural basis for histidine N1-specific methylation by human CARNMT1 3 . Recently, SET domain-containing protein 3 (SETD3) was identified as an N3-specific histidine methyltransferase of β-actin at the highly conserved residue H73 4,5 .…”

Section: O R R E S P O N D E N C E O P E N a C C E S Smentioning

confidence: 99%

“…In the latter case, an acidic residue D316 forms a direct hydrogen bond to N3 of the histidine imidazole ring whose flipping is further constrained by residue H347, thus rendering only N1 available for methylation (Fig. 1hii) 3 . SETD3 adopts a different mechanism to achieve N3-position specificity.…”

Section: O R R E S P O N D E N C E O P E N a C C E S Smentioning

confidence: 99%

Molecular basis for histidine N3-specific methylation of actin H73 by SETD3

Zheng

Zhang

2020

Cell Discov

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“…Hpm1 and SETD3 modify N3-methylhisitidine on specific substrates, Rpl3 and actin, respectively (Webb et al, 2010 ; Wilkinson et al, 2019 ). CARNMT1 is an N1 position-specific methyltransferase that catalyzes dipeptide (Cao et al, 2018 ). However, the methyltransferases that modify N1-methylhisitidine on protein substrates, as well as the functional and (patho)physiological significance of such modification, still remain a major knowledge gap in the field of protein posttranslational modification.…”

mentioning

confidence: 99%