Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1.
Phosphoglycerate mutase (PGAM) is an enzyme of intermediary metabolism that converts 3-phosphoglycerate to 2-phosphoglycerate in glycolysis. Here, we discovered PGAM5 that is anchored in the mitochondrial membrane lacks PGAM activity and instead associates with the MAP kinase kinase kinase ASK1 and acts as a specific protein Ser/Thr phosphatase that activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and phospho-Thr peptides as substrates. The Drosophila and Caenorhabditis elegans orthologs of PGAM5 also exhibit specific Ser/Thr phosphatase activity and activate the corresponding Drosophila and C. elegans ASK1 kinases. PGAM5 is unrelated to the other known Ser/Thr phosphatases of the PPP, MPP, and FCP families, and our results suggest that this member of the PGAM family has crossed over from small molecules to protein substrates and been adapted to serve as a specialized activator of ASK1.
Takeda
Kohsuke
K
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, Global Center of Excellence program, Japan Science and Technology Corporation, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. takeda@mol.f.u-tokyo.ac.jp
Komuro
Yoshiko
Y
Hayakawa
Teruyuki
T
Oguchi
Haruka
H
Ishida
Yosuke
Y
Murakami
Shiori
S
Noguchi
Takuya
T
Kinoshita
Hideyuki
H
Sekine
Yusuke
Y
Iemura
Shun-ichiro
S
Natsume
Tohru
T
Ichijo
Hidenori
H
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D020134:Catalytic Domain / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D017124:Conserved Sequence / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D019143:Evolution, Molecular; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
D002352:Carrier Proteins; D029721:Drosophila Proteins; D024101:Mitochondrial Proteins; D013912:Threonine; D012694:Serine; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C573812:PGAM5 protein, Drosophila; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases