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Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site
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| Zeitschriftentitel: | Protein Science |
|---|---|
| Personen und Körperschaften: | , , , , , , , |
| In: | Protein Science, 13, 2004, 1, S. 155-165 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| author_facet |
Adams, Julian Chen, Zhi‐Ping Van Denderen, Bryce J.W. Morton, Craig J. Parker, Michael W. Witters, Lee A. Stapleton, David Kemp, Bruce E. Adams, Julian Chen, Zhi‐Ping Van Denderen, Bryce J.W. Morton, Craig J. Parker, Michael W. Witters, Lee A. Stapleton, David Kemp, Bruce E. |
|---|---|
| author |
Adams, Julian Chen, Zhi‐Ping Van Denderen, Bryce J.W. Morton, Craig J. Parker, Michael W. Witters, Lee A. Stapleton, David Kemp, Bruce E. |
| spellingShingle |
Adams, Julian Chen, Zhi‐Ping Van Denderen, Bryce J.W. Morton, Craig J. Parker, Michael W. Witters, Lee A. Stapleton, David Kemp, Bruce E. Protein Science Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site Molecular Biology Biochemistry |
| author_sort |
adams, julian |
| spelling |
Adams, Julian Chen, Zhi‐Ping Van Denderen, Bryce J.W. Morton, Craig J. Parker, Michael W. Witters, Lee A. Stapleton, David Kemp, Bruce E. 0961-8368 1469-896X Wiley Molecular Biology Biochemistry http://dx.doi.org/10.1110/ps.03340004 <jats:title>Abstract</jats:title><jats:p>AMP‐activated protein kinase (AMPK) is a αβγ heterotrimer that is activated in response to both hormones and intracellular metabolic stress signals. AMPK is regulated by phosphorylation on the α subunit and by AMP allosteric control previously thought to be mediated by both α and γ subunits. Here we present evidence that adjacent γ subunit pairs of CBS repeat sequences (after <jats:styled-content>C</jats:styled-content>ystathionine <jats:styled-content>B</jats:styled-content>eta <jats:styled-content>S</jats:styled-content>ynthase) form an AMP binding site related to, but distinct from the classical AMP binding site in phosphorylase, that can also bind ATP. The AMP binding site of the γ<jats:sub>1</jats:sub> CBS1/CBS2 pair, modeled on the structures of the CBS sequences present in the inosine monophosphate dehydrogenase crystal structure, contains three arginine residues 70, 152, and 171 and His151. The yeast γ homolog, snf4 contains a His151Gly substitution, and when this is introduced into γ<jats:sub>1</jats:sub>, AMP allosteric control is substantially lost and explains why the yeast snf1p/snf4p complex is insensitive to AMP. Arg70 in γ<jats:sub>1</jats:sub> corresponds to the site of mutation in human γ<jats:sub>2</jats:sub> and pig γ<jats:sub>3</jats:sub> genes previously identified to cause an unusual cardiac phenotype and glycogen storage disease, respectively. Mutation of any of AMP binding site Arg residues to Gln substantially abolishes AMP allosteric control in expressed AMPK holoenzyme. The Arg/Gln mutations also suppress the previously described inhibitory properties of ATP and render the enzyme constitutively active. We propose that ATP acts as an intrasteric inhibitor by bridging the α and γ subunits and that AMP functions to derepress AMPK activity.</jats:p> Intrasteric control of AMPK via the γ<sub>1</sub> subunit AMP allosteric regulatory site Protein Science |
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10.1110/ps.03340004 |
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Online Free |
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Biologie Chemie und Pharmazie |
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Wiley, 2004 |
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Protein Science |
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| title |
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_unstemmed |
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_full |
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_fullStr |
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_full_unstemmed |
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_short |
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_sort |
intrasteric control of ampk via the γ<sub>1</sub> subunit amp allosteric regulatory site |
| topic |
Molecular Biology Biochemistry |
| url |
http://dx.doi.org/10.1110/ps.03340004 |
| publishDate |
2004 |
| physical |
155-165 |
| description |
<jats:title>Abstract</jats:title><jats:p>AMP‐activated protein kinase (AMPK) is a αβγ heterotrimer that is activated in response to both hormones and intracellular metabolic stress signals. AMPK is regulated by phosphorylation on the α subunit and by AMP allosteric control previously thought to be mediated by both α and γ subunits. Here we present evidence that adjacent γ subunit pairs of CBS repeat sequences (after <jats:styled-content>C</jats:styled-content>ystathionine <jats:styled-content>B</jats:styled-content>eta <jats:styled-content>S</jats:styled-content>ynthase) form an AMP binding site related to, but distinct from the classical AMP binding site in phosphorylase, that can also bind ATP. The AMP binding site of the γ<jats:sub>1</jats:sub> CBS1/CBS2 pair, modeled on the structures of the CBS sequences present in the inosine monophosphate dehydrogenase crystal structure, contains three arginine residues 70, 152, and 171 and His151. The yeast γ homolog, snf4 contains a His151Gly substitution, and when this is introduced into γ<jats:sub>1</jats:sub>, AMP allosteric control is substantially lost and explains why the yeast snf1p/snf4p complex is insensitive to AMP. Arg70 in γ<jats:sub>1</jats:sub> corresponds to the site of mutation in human γ<jats:sub>2</jats:sub> and pig γ<jats:sub>3</jats:sub> genes previously identified to cause an unusual cardiac phenotype and glycogen storage disease, respectively. Mutation of any of AMP binding site Arg residues to Gln substantially abolishes AMP allosteric control in expressed AMPK holoenzyme. The Arg/Gln mutations also suppress the previously described inhibitory properties of ATP and render the enzyme constitutively active. We propose that ATP acts as an intrasteric inhibitor by bridging the α and γ subunits and that AMP functions to derepress AMPK activity.</jats:p> |
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| author | Adams, Julian, Chen, Zhi‐Ping, Van Denderen, Bryce J.W., Morton, Craig J., Parker, Michael W., Witters, Lee A., Stapleton, David, Kemp, Bruce E. |
| author_facet | Adams, Julian, Chen, Zhi‐Ping, Van Denderen, Bryce J.W., Morton, Craig J., Parker, Michael W., Witters, Lee A., Stapleton, David, Kemp, Bruce E., Adams, Julian, Chen, Zhi‐Ping, Van Denderen, Bryce J.W., Morton, Craig J., Parker, Michael W., Witters, Lee A., Stapleton, David, Kemp, Bruce E. |
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| description | <jats:title>Abstract</jats:title><jats:p>AMP‐activated protein kinase (AMPK) is a αβγ heterotrimer that is activated in response to both hormones and intracellular metabolic stress signals. AMPK is regulated by phosphorylation on the α subunit and by AMP allosteric control previously thought to be mediated by both α and γ subunits. Here we present evidence that adjacent γ subunit pairs of CBS repeat sequences (after <jats:styled-content>C</jats:styled-content>ystathionine <jats:styled-content>B</jats:styled-content>eta <jats:styled-content>S</jats:styled-content>ynthase) form an AMP binding site related to, but distinct from the classical AMP binding site in phosphorylase, that can also bind ATP. The AMP binding site of the γ<jats:sub>1</jats:sub> CBS1/CBS2 pair, modeled on the structures of the CBS sequences present in the inosine monophosphate dehydrogenase crystal structure, contains three arginine residues 70, 152, and 171 and His151. The yeast γ homolog, snf4 contains a His151Gly substitution, and when this is introduced into γ<jats:sub>1</jats:sub>, AMP allosteric control is substantially lost and explains why the yeast snf1p/snf4p complex is insensitive to AMP. Arg70 in γ<jats:sub>1</jats:sub> corresponds to the site of mutation in human γ<jats:sub>2</jats:sub> and pig γ<jats:sub>3</jats:sub> genes previously identified to cause an unusual cardiac phenotype and glycogen storage disease, respectively. Mutation of any of AMP binding site Arg residues to Gln substantially abolishes AMP allosteric control in expressed AMPK holoenzyme. The Arg/Gln mutations also suppress the previously described inhibitory properties of ATP and render the enzyme constitutively active. We propose that ATP acts as an intrasteric inhibitor by bridging the α and γ subunits and that AMP functions to derepress AMPK activity.</jats:p> |
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| imprint | Wiley, 2004 |
| imprint_str_mv | Wiley, 2004 |
| institution | DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-D161, DE-Zwi2, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1 |
| issn | 1469-896X, 0961-8368 |
| issn_str_mv | 1469-896X, 0961-8368 |
| language | English |
| last_indexed | 2024-03-01T17:01:30.977Z |
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| physical | 155-165 |
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| publisher | Wiley |
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| series | Protein Science |
| source_id | 49 |
| spelling | Adams, Julian Chen, Zhi‐Ping Van Denderen, Bryce J.W. Morton, Craig J. Parker, Michael W. Witters, Lee A. Stapleton, David Kemp, Bruce E. 0961-8368 1469-896X Wiley Molecular Biology Biochemistry http://dx.doi.org/10.1110/ps.03340004 <jats:title>Abstract</jats:title><jats:p>AMP‐activated protein kinase (AMPK) is a αβγ heterotrimer that is activated in response to both hormones and intracellular metabolic stress signals. AMPK is regulated by phosphorylation on the α subunit and by AMP allosteric control previously thought to be mediated by both α and γ subunits. Here we present evidence that adjacent γ subunit pairs of CBS repeat sequences (after <jats:styled-content>C</jats:styled-content>ystathionine <jats:styled-content>B</jats:styled-content>eta <jats:styled-content>S</jats:styled-content>ynthase) form an AMP binding site related to, but distinct from the classical AMP binding site in phosphorylase, that can also bind ATP. The AMP binding site of the γ<jats:sub>1</jats:sub> CBS1/CBS2 pair, modeled on the structures of the CBS sequences present in the inosine monophosphate dehydrogenase crystal structure, contains three arginine residues 70, 152, and 171 and His151. The yeast γ homolog, snf4 contains a His151Gly substitution, and when this is introduced into γ<jats:sub>1</jats:sub>, AMP allosteric control is substantially lost and explains why the yeast snf1p/snf4p complex is insensitive to AMP. Arg70 in γ<jats:sub>1</jats:sub> corresponds to the site of mutation in human γ<jats:sub>2</jats:sub> and pig γ<jats:sub>3</jats:sub> genes previously identified to cause an unusual cardiac phenotype and glycogen storage disease, respectively. Mutation of any of AMP binding site Arg residues to Gln substantially abolishes AMP allosteric control in expressed AMPK holoenzyme. The Arg/Gln mutations also suppress the previously described inhibitory properties of ATP and render the enzyme constitutively active. We propose that ATP acts as an intrasteric inhibitor by bridging the α and γ subunits and that AMP functions to derepress AMPK activity.</jats:p> Intrasteric control of AMPK via the γ<sub>1</sub> subunit AMP allosteric regulatory site Protein Science |
| spellingShingle | Adams, Julian, Chen, Zhi‐Ping, Van Denderen, Bryce J.W., Morton, Craig J., Parker, Michael W., Witters, Lee A., Stapleton, David, Kemp, Bruce E., Protein Science, Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site, Molecular Biology, Biochemistry |
| title | Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_full | Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_fullStr | Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_full_unstemmed | Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_short | Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| title_sort | intrasteric control of ampk via the γ<sub>1</sub> subunit amp allosteric regulatory site |
| title_unstemmed | Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site |
| topic | Molecular Biology, Biochemistry |
| url | http://dx.doi.org/10.1110/ps.03340004 |