The passage of molecules and information across cell membranes is mediated largely by membrane-spanning proteins acting as channels, pumps, receptors and enzymes. These proteins perform many tasks: they control electrochemical gradients across the membrane, receive signals from the environment or from other cells, convert light energy into chemical signals, transport small molecules into and out of cells, and harness proton gradients to generate the energy consumed in metabolism. Indeed, of the estimated 50000–100000 genes in the human genome, fully 20–40 % are thought to encode integral membrane proteins. If one also includes membrane-associated proteins, which are attached to the membrane surface through fatty acyl chains or electrostatic interactions, this percentage is likely to be much higher.
The bovine papillomavirus E5 protein is thought to be a type II integral membrane protein that exists as a disulfide-linked homodimer in transformed cells. Polarized-infrared measurements show that the E5 dimer in membrane bilayers is largely alpha-helical and has a transmembrane orientation. Computational searches of helix-helix conformations reveal two possible low-energy dimer structures. Correlation of these results with previous mutagenesis studies on the E5 protein suggests how the E5 dimer may serve as a molecular scaffold for dimerization and ligand-independent activation of the PDGF-beta receptor. We propose that on each face of the E5 dimer a PDGF-beta receptor molecule interacts directly with Gln17 from one E5 monomer and with Asp33 from the other E5 monomer. This model accounts for the requirement of Gln17 and Asp33 for complex formation and explains genetic results that dimerization of the E5 protein is essential for cell transformation.
The substantial, lanthanide-induced differences in metal-ion and substrate binding to KF exo account for the inhibition of this enzyme by Eu3+. These changes also explain the inability of KF exo to bind more than one cation in the presence of lanthanides. The mechanistic similarity between KF exo and other two-metal-ion phosphoryl-transfer enzymes suggests that the principles of lanthanide (III) ion binding and inhibition ascertained from this study will probably apply to most members of this class of enzymes.
The bovine papillomavirus E5 protein is thought to be a type II integral membrane protein that exists as a disulfide-linked homodimer in transformed cells. Polarized-infrared measurements show that the E5 dimer in membrane bilayers is largely alpha-helical and has a transmembrane orientation. Computational searches of helix-helix conformations reveal two possible low-energy dimer structures. Correlation of these results with previous mutagenesis studies on the E5 protein suggests how the E5 dimer may serve as a molecular scaffold for dimerization and ligand-independent activation of the PDGF-beta receptor. We propose that on each face of the E5 dimer a PDGF-beta receptor molecule interacts directly with Gln17 from one E5 monomer and with Asp33 from the other E5 monomer. This model accounts for the requirement of Gln17 and Asp33 for complex formation and explains genetic results that dimerization of the E5 protein is essential for cell transformation.
Xenotransplantation: how close are we? A group of experts reflects on what was learned from the first human transplants of genetically engineered pig organs and what the future of xenotransplantation may hold.X enotransplantation research marked a singular milestone last year with the first human transplants of kidneys and a heart from genetically engineered pigs. The genetic modifications were designed to improve transplantation outcomes by lessening immune rejection, controlling organ size and regulating complement, coagulation and inflammation. These pioneering surgeries were motivated by deficiencies of the current donor organ system, which have led to long waiting lists for organs (Fig. 1) and the deaths of thousands of patients in need of organs each year. Pig kidneys were transplanted into three brain-dead recipients -one at Legacy of Hope, University of Alabama 1 and two at New York University Langone Hospital 2 . A pig heart was transplanted into a living recipient at University of Maryland School of Medicine 3 . The donor pigs, supplied by Revivicor, had either one gene knockout or a set of ten gene knockouts and transgenes (Table 1). What have we learned from these experiences, and how will they guide future research and surgical practice in the field? Are phase 1 clinical trials on the horizon? Experts in transplantation medicine, immunology and virology discuss the present state and future prospects of xenotransplantation.
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