Glucose regulates protein interactions within the yeast SNF1 protein kinase complex.

Jiang, Rong; Carlson, Marian

doi:10.1101/gad.10.24.3105

Cited by 266 publications

(338 citation statements)

References 55 publications

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“…The interaction between Snf4p and Snf1p is also influenced by the catalytic activity of Snf1p. Whereas in active Snf1p the residues 392-495 bind Snf4p, the Snf1p residues 392-518 are required for kinase-dead Snf1p to bind Snf4 (25). The intervening Snf1p sequence 495-518 contains the highly conserved GIRSQSYPL sequence in ␣ containing Ser-404 (underlined) as part of a putative 14.3.3-binding site (1), but it is not known whether this site is phosphorylated or influences Snf4p binding.…”

Section: Discussionmentioning

confidence: 99%

AMP-activated Protein Kinase β Subunit Tethers α and γ Subunits via Its C-terminal Sequence (186–270)

Iseli

Walter

Denderen

et al. 2005

Journal of Biological Chemistry

125

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AMP-activated protein kinase (AMPK) is an important metabolic stress-sensing protein kinase responsible for regulating metabolism in response to changing energy demand and nutrient supply. Mammalian AMPK is a stable ␣␤␥ heterotrimer comprising a catalytic ␣ and two non-catalytic subunits, ␤ and ␥. The ␤ subunit targets AMPK to membranes via an N-terminal myristoyl group and to glycogen via a mid-molecule glycogen-binding domain. Here we find that the conserved C-terminal 85-residue sequence of the ␤ subunit, ␤1-(186 -270), is sufficient to form an active AMP-dependent heterotrimer ␣1␤1- AMPK 1 is a multi-substrate enzyme that is activated in response to both hormones and intracellular metabolic stress generated by exercise, hypoxia, and nutrient deprivation. There are multiple isoforms of each AMPK subunit, with ␣1, ␣2, ␤1, ␤2, ␥1, ␥2, and ␥3 forming heterotrimers that differ in tissue and subcellular localization (reviewed in Ref. 1). The ␣ subunit contains an N-terminal catalytic core (1-312) and a C-terminal sequence (313-548) responsible for autoregulation and binding the ␤␥ subunits (2). Maximum activity requires all three subunits (3). The catalytic AMPK ␣1-(1-312) fragment is constitutively active whereas the ␣1-(1-392) fragment is autoinhibited, and neither bind ␤␥ subunits (2). The three ␥ subunits each contain four CBS sequence repeats that were named after the corresponding sequences in cystathionine ␤-synthase (CBS) along with variable N-terminal extensions (4). AMP binds to the ␥ subunit and is responsible for the allosteric regulation of AMPK (5). There are two binding sites for AMP formed by the CBS1/2 and CBS3/4 sequence pairs (5), and because pairs of the CBS sequences form a discrete functional structure, they have now been termed Bateman modules (6). The ␤ subunit N-terminal myristoyl group is responsible for targeting AMPK to the membrane (7), and an internal glycogen-binding domain (68 -163) targets AMPK to glycogen (8, 9).The AMPK ␣ subunit is a homolog of yeast Snf1p kinase (10), which also binds ␤␥ subunit homologs (11, 12). There are three yeast ␤ subunit homologs, Gal83p, Sip1p, and Sip2p, and a single ␥ subunit homolog, Snf4p (13). In contrast to mammalian AMPK, which requires all three subunits for optimal activity (3), Snf1p/Snf4p forms a stable active complex that can be readily isolated from bakers' yeast without a ␤ homolog (Gal83p, Sip1p, or Sip2p) (11,14). Deletion of either Snf1p or Snf4p blocks growth on sucrose, as does deletion of all three ␤ subunit homologs (15). Studies of the subunit interactions in yeast using the two-hybrid approach have identified two regions within the yeast ␤ homologs termed KIS (kinase interacting sequence) and ASC (association with Snf1p complex), respectively. The C-terminal 85-residue ASC sequence of Gal83p was shown to bind Snf4p by two-hybrid analysis (13). The internal KIS sequence of Gal83p, Sip1p, or Sip2p interacted with the non-catalytic C terminus of Snf1p (13). In contrast, studies on mammalian AMPK have shown that the corresponding int...

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Section: Discussionmentioning

confidence: 99%

AMP-activated Protein Kinase β Subunit Tethers α and γ Subunits via Its C-terminal Sequence (186–270)

Iseli

Walter

Denderen

et al. 2005

Journal of Biological Chemistry

125

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“…When high levels of glucose are present, an auto-inhibitory interaction between the N-terminal catalytic domain and the C-terminal regulatory domain of Snf1 inactivates the protein kinase. This autoinhibition is relieved when glucose levels drop, which correlates with an increased interaction between the c subunit Snf4 and the Snf1 regulatory domain (Jiang and Carlson 1996).…”

Section: Structure and Regulation Of The Snf1 Kinasementioning

confidence: 99%

“…Two other hexokinases, Hxk1 and Glk1, can also catalyse this reaction, but Hxk2 is believed to be the crucial hexokinase during growth on glucose, since Hxk1 and Glk1 are themselves subject to glucose repression (De Winde et al 1996). It was reported that in a hxk2D mutant, the glucose repression of several genes was severely reduced (Zimmermann and Scheel 1977;Entian 1980;Entian and Zimmermann 1980), the interaction between Snf1 and Snf4 was increased (Jiang and Carlson 1996;Sanz et al 2000) and that Snf1 still phosphorylated Mig1 in the presence of glucose (Treitel et al 1998;Ahuatzi et al 2007). Early reports suggested that the role of Hxk2 in glucose repression was limited to its metabolic role (Ma et al 1989;Rose et al 1991).…”

Section: Transducing the Glucose Signal To Snf1mentioning

confidence: 99%

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

et al. 2010

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Cells of all living organisms contain complex signal transduction networks to ensure that a wide range of physiological properties are properly adapted to the environmental conditions. The fundamental concepts and individual building blocks of these signalling networks are generally well-conserved from yeast to man; yet, the central role that growth factors and hormones play in the regulation of signalling cascades in higher eukaryotes is executed by nutrients in yeast. Several nutrient-controlled pathways, which regulate cell growth and proliferation, metabolism and stress resistance, have been defined in yeast. These pathways are integrated into a signalling network, which ensures that yeast cells enter a quiescent, resting phase (G 0 ) to survive periods of nutrient scarceness and that they rapidly resume growth and cell proliferation when nutrient conditions become favourable again. A series of well-conserved nutrient-sensory protein kinases perform key roles in this signalling network: i.e. Snf1, PKA, Tor1 and Tor2, Sch9 and Pho85-Pho80. In this review, we provide a comprehensive overview on the current understanding of the signalling processes mediated via these kinases with a particular focus on how these individual pathways converge to signalling networks that ultimately ensure the dynamic translation of extracellular nutrient signals into appropriate physiological responses.

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“…6A), indicating that the mutated Snf4 is capable of forming a functionally competent SNF1 complex in vivo. Snf4 interacts with Snf1, and this interaction is markedly increased in glucose-deprived cells (27). We examined the interaction of wildtype and mutant Snf4 with Snf1 in the two-hybrid system.…”

Section: Figmentioning

confidence: 99%

Functional Analysis of Mutations in the γ2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome

Daniel

Carling

2002

Journal of Biological Chemistry

111

100

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Mutations in the gene encoding the ␥ 2 subunit of the AMP-activated protein kinase (AMPK) have recently been shown to cause cardiac hypertrophy and ventricular pre-excitation (Wolff-Parkinson-White syndrome). We have examined the effect of four of these mutations on AMPK activity. The mutant ␥ 2 polypeptides are all able to form functional complexes following co-expression with either ␣ 1 ␤ 1 or ␣ 2 ␤ 1 in mammalian cells. None of the mutations caused any detectable change in the phosphorylation of threonine 172 within the ␣ subunit of AMPK. Consequently, in the absence of an appropriate stimulus the mutant complexes, like the wild-type complex, exist in an inactive form demonstrating that the mutations do not lead to constitutive activation of the kinase. Three of the mutations we studied occur within the cystathionine ␤-synthase (CBS) domains of ␥ 2 . Two of these mutations lead to a marked decrease in AMP dependence, whereas the third reduces AMP sensitivity. These findings suggest that the CBS domains play an important role in AMP-binding within the complex. In contrast, a fourth mutation, which lies between adjacent CBS domains, has no significant effect on AMPK activity in vitro. These results indicate that mutations in ␥ 2 have different effects on AMPK function, suggesting that they may lead to abnormal development of the heart through distinct mechanisms.The AMP-activated protein kinase (AMPK) 1 is the central component of a protein kinase cascade that plays a pivotal role in the regulation of energy metabolism (1). In response to activation following an increase in the AMP/ATP ratio, AMPK phosphorylates a number of downstream targets culminating in the switching off of energy (ATP)-utilizing pathways and the switching on of energy-generating pathways (1, 2). Activation of AMPK is complex and involves direct allosteric activation of the enzyme by AMP as well as phosphorylation, catalyzed by an upstream kinase, AMPK kinase (AMPKK) (3, 4). AMPK is a heterotrimeric complex, consisting of a catalytic subunit (␣) and two regulatory subunits (␤ and ␥) (5, 6) and isoforms of all three subunits have been identified (7-9). Although there is compelling evidence indicating that formation of the heterotrimeric complex is necessary for significant kinase activity (6, 10) the precise role of the regulatory subunits remains unclear. In addition, at present our understanding of the physiological relevance of the different subunit isoforms is very limited.Several groups have reported recently the identification of six different mutations in the ␥2 subunit from patients with cardiac hypertrophy and associated electrophysiologic abnormalties (11-14). All six mutations result in amino acid substitutions and are located within the C-terminal half of the protein. The mutations lead to the development of aberrant conduction systems, including pre-excitation, characteristic of Wolff-Parkinson-White syndrome (15) and in all but one case, the mutations also result in severe cardiac hypertrophy. No evidence of cardiac hypertro...

show abstract

Glucose regulates protein interactions within the yeast SNF1 protein kinase complex.

Cited by 266 publications

References 55 publications

AMP-activated Protein Kinase β Subunit Tethers α and γ Subunits via Its C-terminal Sequence (186–270)

AMP-activated Protein Kinase β Subunit Tethers α and γ Subunits via Its C-terminal Sequence (186–270)

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

Functional Analysis of Mutations in the γ2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome

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