Biomedical subjects

Andreas Förster

Publications and source records attributed to Andreas Förster.

5 recordsLinked to original sources

PubMed2006

Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial.

BACKGROUND: Recent clinical trials have suggested that intensive versus standard lipid-lowering therapy provides for additional benefit. Electron-beam computed tomography provides the opportunity to quantify the progression of coronary artery calcification (CAC) in serial measurements. METHODS AND RESULTS: In a multicenter, randomized, double-blind trial, 471 patients (age 61+/-8 years) who had no history of coronary artery disease and no evidence of high-grade coronary stenoses (>50% diameter reduction) were randomized if they had > or =2 cardiovascular risk factors and moderate calcified coronary atherosclerosis as evidenced by a CAC score > or =30. Patients were assigned to receive 80 mg or 10 mg of atorvastatin per day over 12 months. Progression of CAC volume scores could be analyzed in 366 patients. After pretreatment with 10 mg of atorvastatin for 4 weeks, 12 months of study medication reduced LDL cholesterol from 106+/-22 to 87+/-33 mg/dL in the group randomized to receive 80 mg of atorvastatin (P<0.001), whereas levels remained stable in the group randomized to receive 10 mg (108+/-23 at baseline, 109+/-28 mg/dL at the end of the study, P=NS). The mean progression of CAC volume scores, corrected for the baseline CAC volume score, was 27% (95% CI 20.8% to 33.1%) in the 80-mg atorvastatin group and 25% (95% CI 19.1% to 30.8%) in the 10-mg atorvastatin group (P=0.65). CAC progression showed no relationship with on-treatment LDL cholesterol levels. CONCLUSIONS: We did not observe a relationship between on-treatment LDL cholesterol levels and the progression of calcified coronary atherosclerosis. Over a period of 12 months, intensive atorvastatin therapy was unable to attenuate CAC progression compared with standard atorvastatin therapy. The possibility remains that the time window was too short to demonstrate an effect.

Adult↗

PubMed2005

The 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700 interactions.

Proteasomes are cylindrical structures that function in multiple cellular processes by degrading a wide variety of cytosolic and nuclear proteins. Substrate access and product release from the enclosed catalytic chamber occurs through axial pores that are opened by activator complexes. Here, we report high-resolution structures of wild-type and mutant archaeal proteasomes bound to the activator PA26. These structures support the proposal that an ordered open conformation is required for proteolysis and that its formation can be triggered by outward displacement of surrounding residues. The structures and associated biochemical assays reveal the mechanism of binding, which involves an interaction between the PA26 C terminus and a conserved lysine. Surprisingly, biochemical observations implicate an equivalent interaction for the unrelated ATP-dependent activators PAN and PA700.

Amino Acid Sequence↗

PubMed2005

Purification and analysis of recombinant 11S activators of the 20S proteasome: Trypanosoma brucei PA26 and human PA28 alpha, PA28 beta, and PA28 gamma.

Proteasomes perform the bulk of nonlysosomal degradation of aberrant, damaged, misfolded, and naturally short-lived regulatory proteins in eukaryotic cells. They are approximately 700-kDa assemblies whose hollow architecture sequesters the proteolytic sites inside a central chamber, thereby ensuring that the activity of isolated proteasomes is repressed. In vivo, proteasomes are activated by protein complexes, including the 11S activators (PA28 and PA26), which bind to one or both ends of the barrel-shaped structure. This chapter describes protocols for the purification of recombinant 11S regulators, characterization of their ability to stimulate proteasome activity, and crystallization of proteasome complexes.

Animals↗

PubMed2003

The pore of activated 20S proteasomes has an ordered 7-fold symmetric conformation.

The 20S proteasome is a large multisubunit assembly that performs most of the intracellular non-lysosomal proteolysis of eukaryotes. Substrates access the proteasome active sites, which are sequestered in the interior of the barrel-shaped structure, through pores that are opened by binding of activator complexes. The crystal structure of yeast proteasome in complex with an 11S activator suggested that activation results from disordering of the proteasome gate residues. Here we report further analysis of this structure, which demonstrates that, in contrast to earlier models, the activated proteasome adopts an ordered 7-fold symmetric pore conformation that is stabilized by interactions formed by a cluster of highly conserved proteasome residues (Tyr8, Asp9, Pro17 and Tyr26). One non-canonical cluster, which appears to be mandated by the requirement that eukaryotic proteasomes also form an ordered closed conformation, explains all deviations from perfect conservation of these residues. We also demonstrate the importance of these conserved residues for proteolysis by an archaeal proteasome. Evolutionary considerations suggest that other activators might induce the same open proteasome conformation as seen with the 11S activator.

Amino Acid Sequence↗

PubMed2003

Proteasome degradation: enter the substrate.

Cells depend upon the regulated destruction of their various proteins to maintain homeostasis and change their metabolic state. A key component of this process is the proteasome - a large multisubunit protease whose catalytic sites are sequestered within a central chamber. Entry of substrates into proteasomes is regulated by activators and is generally thought to proceed sequentially, starting from one end of the substrate polypeptide. This conventional view is expanded by a recent paper, which indicates that some unfolded substrates can open the entrance to the proteolytic chamber in the absence of an activator and can enter the proteasome in a hairpin conformation to allow limited proteolysis of internal segments.

Animals↗