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Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

Abstract

There is an increasing body of evidence for local circuits of ATP generation and consumption that are largely independent of global cellular ATP levels. These are mostly based on the formation of multiprotein(-lipid) complexes and diffusion limitations existing in cells at different levels of organization, e.g., due to the viscosity of the cytosolic medium, macromolecular crowding, multiple and bulky intracellular structures, or controlled permeability across membranes. Enzymes generating ATP or GTP are found associated with ATPases and GTPases enabling the direct fueling of these energy-dependent processes, and thereby implying that it is the local and not the global concentration of high-energy metabolites that is functionally relevant. A paradigm for such microcompartmentation is creatine kinase (CK). Cytosolic and mitochondrial isoforms of CK constitute a well established energy buffering and shuttling system whose functions are very much based on local association of CK isoforms with ATP-providing and ATP-consuming processes. Here we review current knowledge on the subcellular localization and direct protein and lipid interactions of CK isoforms, in particular about cytosolic brain-type CK (BCK) much less is known compared to muscle-type CK (MCK). We further present novel data on BCK, based on three different experimental approaches: (1) co-purification experiments, suggesting association of BCK with membrane structures such as synaptic vesicles and mitochondria, involving hydrophobic and electrostatic interactions, respectively; (2) yeast-two-hybrid analysis using cytosolic split-protein assays and the identifying membrane proteins VAMP2, VAMP3 and JWA as putative BCK interaction partners; and (3) phosphorylation experiments, showing that the cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate BCK at serine 6 to trigger BCK localization at the ER, in close vicinity of the highly energy-demanding Ca2+ ATPase pump. Thus, membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations.

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Acknowledgments

We thank Drs. Nicolas Lentze and Daniel Auerbach (both formerly at Dual Systems, Dualsystems Biotech, Schlieren, Switzerland) for providing their proprietary Y2H systems, experimental support and initial discussions. We also thank present and former members of LBFA-Inserm U1055 involved in the studies presented here for their valuable contributions, notably Prof. emer. Valdur Saks. In particular we would like to thank Prof. emer. Theo Wallimann (Zurich, Switzerland) for his long-lasting encouragement and support, as well as the many fruitful discussions. Profs. T. Wallimann and R. Harris are also acknowledged for their editorial work. The work by the authors described herein was supported among others by the EU 6 and 7th framework programs (contract LSHM-CT-2004-005272 EXGENESIS, and contracts ANTHRAWES no. 041870 and ANTHRAPLUS no. 249202 to M.T.S.), the Agence Nationale de Recherche (France, “chaire d’excellence” to U.S., and SYBECAR no. RA0000C407), the Fondation pour la Recherche Médicale (France, to A.K.), and CONACYT (Mexico, contract no. 183832, to S.R.).

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Schlattner, U., Klaus, A., Ramirez Rios, S. et al. Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites. Amino Acids 48, 1751–1774 (2016). https://doi.org/10.1007/s00726-016-2267-3

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Keywords

  • Interactomics
  • Local fueling
  • Microcompartments
  • Channeling
  • Protein complexes