Abstract
S-adenosylmethionine (SAM) is an essential metabolite that acts as a cofactor for most methylation events in the cell. The N6-methyladenosine (m6A) methyltransferase METTL16 controls SAM homeostasis by regulating the abundance of SAM synthetase MAT2A mRNA in response to changing intracellular SAM levels. Here we present crystal structures of METTL16 in complex with MAT2A RNA hairpins to uncover critical molecular mechanisms underlying the regulated activity of METTL16. The METTL16-RNA complex structures reveal atomic details of RNA substrates that drive productive methylation by METTL16. In addition, we identify a polypeptide loop in METTL16 near the SAM binding site with an autoregulatory role. We show that mutations that enhance or repress METTL16 activity in vitro correlate with changes in MAT2A mRNA levels in cells. Thus, we demonstrate the structural basis for the specific activity of METTL16 and further suggest the molecular mechanisms by which METTL16 efficiency is tuned to regulate SAM homeostasis. Doxtader et al. determine crystal structures of the N6-methyladenosine methyltransferase METTL16 in complex with RNA substrates. METTL16 can be regulated by the conformation of the RNA substrate and by an autoregulatory loop near the SAM binding pocket. Modulating the catalytic activity of METTL16 changes MAT2A mRNA levels in cells.
| Original language | English (US) |
|---|---|
| Journal | Molecular Cell |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- MAT2A
- metabolism
- methyltransferase
- METTL14
- METTL16
- METTL3
- N6-methyladenosine (m6A)
- S-adenosylmethionine (SAM)
- SAM homeostasis
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
Structural Basis for Regulation of METTL16, an S-Adenosylmethionine Homeostasis Factor. / Doxtader, Katelyn A.; Wang, Ping; Scarborough, Anna M.; Seo, Dahee; Conrad, Nicholas K.; Nam, Yunsun.
In: Molecular Cell, 01.01.2018.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Structural Basis for Regulation of METTL16, an S-Adenosylmethionine Homeostasis Factor
AU - Doxtader, Katelyn A.
AU - Wang, Ping
AU - Scarborough, Anna M.
AU - Seo, Dahee
AU - Conrad, Nicholas K.
AU - Nam, Yunsun
PY - 2018/1/1
Y1 - 2018/1/1
N2 - S-adenosylmethionine (SAM) is an essential metabolite that acts as a cofactor for most methylation events in the cell. The N6-methyladenosine (m6A) methyltransferase METTL16 controls SAM homeostasis by regulating the abundance of SAM synthetase MAT2A mRNA in response to changing intracellular SAM levels. Here we present crystal structures of METTL16 in complex with MAT2A RNA hairpins to uncover critical molecular mechanisms underlying the regulated activity of METTL16. The METTL16-RNA complex structures reveal atomic details of RNA substrates that drive productive methylation by METTL16. In addition, we identify a polypeptide loop in METTL16 near the SAM binding site with an autoregulatory role. We show that mutations that enhance or repress METTL16 activity in vitro correlate with changes in MAT2A mRNA levels in cells. Thus, we demonstrate the structural basis for the specific activity of METTL16 and further suggest the molecular mechanisms by which METTL16 efficiency is tuned to regulate SAM homeostasis. Doxtader et al. determine crystal structures of the N6-methyladenosine methyltransferase METTL16 in complex with RNA substrates. METTL16 can be regulated by the conformation of the RNA substrate and by an autoregulatory loop near the SAM binding pocket. Modulating the catalytic activity of METTL16 changes MAT2A mRNA levels in cells.
AB - S-adenosylmethionine (SAM) is an essential metabolite that acts as a cofactor for most methylation events in the cell. The N6-methyladenosine (m6A) methyltransferase METTL16 controls SAM homeostasis by regulating the abundance of SAM synthetase MAT2A mRNA in response to changing intracellular SAM levels. Here we present crystal structures of METTL16 in complex with MAT2A RNA hairpins to uncover critical molecular mechanisms underlying the regulated activity of METTL16. The METTL16-RNA complex structures reveal atomic details of RNA substrates that drive productive methylation by METTL16. In addition, we identify a polypeptide loop in METTL16 near the SAM binding site with an autoregulatory role. We show that mutations that enhance or repress METTL16 activity in vitro correlate with changes in MAT2A mRNA levels in cells. Thus, we demonstrate the structural basis for the specific activity of METTL16 and further suggest the molecular mechanisms by which METTL16 efficiency is tuned to regulate SAM homeostasis. Doxtader et al. determine crystal structures of the N6-methyladenosine methyltransferase METTL16 in complex with RNA substrates. METTL16 can be regulated by the conformation of the RNA substrate and by an autoregulatory loop near the SAM binding pocket. Modulating the catalytic activity of METTL16 changes MAT2A mRNA levels in cells.
KW - MAT2A
KW - metabolism
KW - methyltransferase
KW - METTL14
KW - METTL16
KW - METTL3
KW - N6-methyladenosine (m6A)
KW - S-adenosylmethionine (SAM)
KW - SAM homeostasis
UR - http://www.scopus.com/inward/record.url?scp=85052758297&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052758297&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2018.07.025
DO - 10.1016/j.molcel.2018.07.025
M3 - Article
C2 - 30197297
AN - SCOPUS:85052758297
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
ER -