Protein Structure and Folding
To be there when the picture is being painted
There is nothing quite like the excitement of discovery in science—of finding something no one else knew and seeing a story unfold. One has to be part of an emerging picture to feel the elation. These moments in a lifetime are few and far between, but they fuel enthusiasm and keep one going. They are embedded in struggles and joys of everyday life, years of establishing what Louis Pasteur called “the prepared mind,” working with mentors, trainees, and colleagues, failures and successes. This article recalls 1) how I got to be a biochemist; 2) my contributions as an educator and researcher, especially regarding meprin metalloproteases; and 3) my participation in communities of science.Separating cytokine twins with a small molecule
The 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 size
A 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.Integrated multidisciplinarity in the natural sciences
The integration of multiple perspectives in both the arts and natural sciences is tremendously powerful and arguably necessary for capturing relevant features of complex phenomena. Individual methods and models comprise abstractions from and idealizations of nature, and only the integration of multiple models, methods, and representations provides a means to reach more accurate results than relying on any single approach. In my Mildred Cohn Award Lecture at the 2019 ASBMB meeting, I illustrated the power of such multidisciplinary work by highlighting the successful integration of data and multiple views afforded by NMR spectroscopy, cryo-electron microscopy, cryo-electron tomography, X-ray crystallography, computation, and functional assays made possible through collaborative efforts by members of the Pittsburgh Center for HIV Protein Interactions.Chloride to the rescue
On 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” membranes
Some 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.
