A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias.
The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that is activated by low cellular energy status and affects a switch away from energy-requiring processes and toward catabolism. While it is primarily regulated by AMP and ATP, high muscle glycogen has also been shown to repress its activation. Mutations in the gamma2 and gamma3 subunit isoforms lead to arrhythmias associated with abnormal glycogen storage in human heart and elevated glycogen in pig muscle, respectively. A putative glycogen binding domain (GBD) has now been identified in the beta subunits. Coexpression of truncated beta subunits lacking the GBD with alpha and gamma subunits yielded complexes that were active and normally regulated. However, coexpression of alpha and gamma with full-length beta caused accumulation of AMPK in large cytoplasmic inclusions that could be counterstained with anti-glycogen or anti-glycogen synthase antibodies. These inclusions were not affected by mutations that increased or abolished the kinase activity and were not observed by using truncated beta subunits lacking the GBD. Our results suggest that the GBD binds glycogen and can lead to abnormal glycogen-containing inclusions when the kinase is overexpressed. These may be related to the abnormal glycogen storage bodies seen in heart disease patients with gamma2 mutations.
Division of Molecular Physiology, Faculty of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Dow Street, Scotland, United Kingdom.
Emma R
ER
Hudson
David A
DA
Pan
John
J
James
John M
JM
Lucocq
Simon A
SA
Hawley
Kevin A
KA
Green
Otto
O
Baba
Tatsuo
T
Terashima
D Grahame
DG
Hardie
D055372:AMP-Activated Protein Kinases; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
D009097:Multienzyme Complexes; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D006003:Glycogen; D006006:Glycogen Synthase; C526225:PRKAG3 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases