Protein Structure and Folding
Separating cytokine twins with a small moleculeThe cytokine macrophage migration inhibitory factor (MIF) has been characterized as a key immunomodulator and mediator of various diseases. Small molecule inhibitors based on the conserved enzymatic pocket of MIF have been valuable in elucidating MIF mechanisms and developing translational strategies. In contrast, our mechanistic understanding of the MIF homolog MIF-2/d-dopachrome tautomerase (d-DT) and its clinical translation has been hampered, partly because MIF-2–selective inhibitors have been elusive.
Cutting antigenic peptides down to sizeA critical step in antigen presentation is the degradative processing of peptides by aminopeptidases in the endoplasmic reticulum. It is unclear whether these enzymes act only on free peptides or on those bound to their major histocompatibility complex (MHC)-I–presenting molecules. A recent study examined the structure and biophysics of N-terminally extended peptides in complex with MHC-I, revealing the conformational adjustment of MHC to permit both binding of the peptide core and exposure of the peptide N terminus.
Chloride to the rescueOn the fiftieth anniversary of the discovery of the Ser-His-Asp catalytic triad, perhaps the most unusual variation on the textbook classic is described: An incomplete catalytic triad in a hydrolase is rescued by a chloride ion (Fig. 1). Structural and functional data provide compelling evidence that the active site of a phospholipase from Vibrio vulnificus employs the anion in place of the commonly observed Asp, reminding us that even well-trodden scientific ground has surprises in store.
Solving the mystery of “leaky” membranesSome cells, such as red blood cells, readily transport water, whereas the water permeability of other cells, such as neurons, is nearly undetectable. For years, researchers wondered why water transport seems to occur in some tissues but not in others. Was there an ion-transport channel doing double-duty as a water channel, or did proteins expressed in certain membranes make them leaky to water? The mystery remained until 1992, when, for the first time, Peter Agre and colleagues identified a dedicated water channel protein, aquaporin-1 (AQP-1)—work that earned Agre the Nobel Prize in 2003.