The structures of F1-ATPase from bovine heart mitochondria inhibited with the dietary phytopolyphenol, resveratrol, and with the related polyphenols quercetin and piceatannol have been determined at 2.3-, 2.4-and 2.7-Å resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three ␣-and three -subunits beneath the ''crown'' of -strands in their N-terminal domains. This region of F 1-ATPase forms a bearing to allow the rotation of the tip of the ␥-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C-terminal tip of the ␥-subunit and the TP subunit, and the inhibitors are bound via H-bonds mostly to their hydroxyl moieties mediated by bound water molecules and by hydrophobic interactions. There are no equivalent sites between the ␥-subunit and either the DP or the E subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the ␥-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis. mitochondria ͉ oxidative phosphorylation ͉ rotary mechanism ͉ crystal structure
The structure of bovine F1-ATPase inhibited by a monomeric form of the inhibitor protein, IF 1, known as I1-60His, lacking most of the dimerization region, has been determined at 2.1-Å resolution. The resolved region of the inhibitor from residues 8 -50 consists of an extended structure from residues 8 -13, followed by two ␣-helices from residues 14 -18 and residues 21-50 linked by a turn. ATP synthase ͉ inhibitor protein ͉ regulation ͉ structure
S100A1, a Ca2؉ -sensing protein of the EF-hand family that is expressed predominantly in cardiac muscle, plays a pivotal role in cardiac contractility in vitro and in vivo. It has recently been demonstrated that by restoring Ca 2؉ homeostasis, S100A1 was able to rescue contractile dysfunction in failing rat hearts. Myocardial contractility is regulated not only by Ca 2؉ homeostasis but also by energy metabolism, in particular the production of ATP. Here, we report a novel interaction of S100A1 with mitochondrial F 1 -ATPase, which affects F 1 -ATPase activity and cellular ATP production. In particular, cardiomyocytes that overexpress S100A1 exhibited a higher ATP content than control cells, whereas knockdown of S100A1 expression decreased ATP levels. In pull-down experiments, we identified the ␣-and -chain of F 1 -ATPase to interact with S100A1 in a Ca 2؉ -dependent manner. The interaction was confirmed by colocalization studies of S100A1 and F 1 -ATPase and the analysis of the S100A1-F 1 -ATPase complex by gel filtration chromatography. The functional impact of this association is highlighted by an S100A1-mediated increase of F 1 -ATPase activity. Consistently, ATP synthase activity is reduced in cardiomyocytes from S100A1 knockout mice. Our data indicate that S100A1 might play a key role in cardiac energy metabolism. S100 proteins are a family of soluble, EF-hand Ca 2ϩ -binding proteins which exhibit a remarkable cell-and tissue-specific expression pattern. They are involved in numerous intracellular activities, such as cell proliferation and differentiation, or the dynamics of cytoskeletal constituents (reviewed in references 4, 9, and 30). The most abundant S100 protein in the heart is S100A1 (12; reviewed in reference 4). It has been recognized recently as a positive inotropic intracellular regulator of cardiac as well as skeletal muscle Ca 2ϩ homeostasis and contractility (15,16,18,19,20). Accordingly, S100A1-deficient mice exhibited an impaired cardiac contractility response to hemodynamic stress (5). Notably, the absence of S100A1 significantly accelerates the development of contractile dysfunction after myocardial infarction, with a rapid onset of cardiac remodeling and a transition to heart failure combined with excessive mortality (21). Normal contractile function and Ca 2ϩ homeostasis, on the other hand, could be restored in failing myocardium in postinfarcted rat hearts by S100A1 gene delivery (19).In addition to Ca 2ϩ homeostasis, myocardial workload depends on cardiac metabolism. As the energy demand changes, the flux through the mitochondrial ATP synthase (F 1 F oATPase), which is responsible for the bulk of ATP synthesis in the myocardium, must change so that ATP synthesis matches ATP consumption (reviewed in references 6 and 10). To sustain cardiac function in all possible situations, there has to be a strict correlation between energy production, energy transfer, and energy utilization (reviewed in reference 29). In this regard, Ca 2ϩ has emerged as a major factor for adapting mitochondrial A...
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