Bak Conformational Changes Induced by Ligand Binding: Insight into BH3 Domain Binding and Bak Homo-Oligomerization

Recently we reported that the BH3-only proteins Bim and Noxa bind tightly but transiently to the BH3-binding groove of Bak to initiate Bak homo-oligomerization. However, it is unclear how such tight binding can induce Bak homo-oligomerization. Here we report the ligand-induced Bak conformational changes observed in 3D models of Noxa·Bak and Bim·Bak refined by molecular dynamics simulations. In particular, upon binding to the BH3-binding groove, Bim and Noxa induce a large conformational change of the loop between helices 1 and 2 and in turn partially expose a remote groove between helices 1 and 6 in Bak. These observations, coupled with the reported experimental data, suggest formation of a pore-forming Bak octamer, in which the BH3-binding groove is at the interface on one side of each monomer and the groove between helices 1 and 6 is at the interface on the opposite side, initiated by ligand binding to the BH3-binding groove

Relationship between renal and cardiovascular changes in a murine model of glucose intolerance

Nutrition is an important variable which may affect the risk for renal disease. We previously showed that a high fructose diet in mice produced hypertension and sympathetic activation [8]. The purpose of this study was to determine if a fructose diet altered renal function. A high fructose diet for 12 weeks impaired glucose tolerance, but caused no change in body weight, blood glucose or plasma insulin. Impairment in renal function was documented by the almost two fold increase in urinary protein excretion (Control: 6.6 +/- 0.6 vs. Fructose: 15.0 +/- 0.7 mmol protein/mmol creatinine; p < 0.05) which was also accompanied by increases in urinary volume. The diet produced little change in renal histology, kidney weight or kidney weight/body weight ratio. Urinary excretion of angiotensin II/creatinine (Control: 78.9 +/- 16.6 vs. Fructose: 80.5 +/- 14.2 pg/mmol) and renal angiotensin converting enzyme activity (Control: 9.2 +/- 1.6 vs. Fructose: 7.6 +/- 1.0 ACE units) were not different between groups. There was a positive correlation between mean arterial pressure (r = 0.7, p = 0.01), blood pressure variability (BPV) (r = 0.7, p = 0.02), low frequency BPV component (r = 0.677, p = 0.03) and urinary protein excretion. Results show that consumption of a high fructose diet in mice had deleterious effects on renal function, which were correlated with cardiovascular changes. (c) 2007 Published by Elsevier B.V.139416991