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Erythroderma presents as generalized skin redness. The features of a 39-year-old man who presented with erythroderma are described. His skin biopsy revealed hyphae in the stratum corneum, which established the diagnosis of tinea corporis. His erythroderma resolved following treatment with an oral antifungal agent. Several conditions can be associated with erythroderma. Common etiologies for erythroderma include medications, neoplasms, and papulosquamous disorders. Superficial dermatophyte-associated erythroderma is rare. However, although erythroderma caused by generalized superficial mycosis is infrequently encountered, tinea corporis should be included in the new-onset or chronic erythroderma. The detection of fungal hyphae in the stratum corneum of a biopsy of the erythrodermic skin can not only establish dermatophyte infection as the underlying cause of the individual’s erythroderma but also an alternative cause of erythroderma.

SWELL1 (LRRC8A) is the only essential subunit of the Volume Regulated Anion Channel (VRAC), which regulates cellular volume homeostasis and is activated by hypotonic solutions. SWELL1, together with four other LRRC8 family members, potentially forms a vastly heterogeneous cohort of VRAC channels with different properties; however, SWELL1 alone is also functional. Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. The structure reveals a trimer of dimers assembly with symmetry mismatch between the pore-forming domain and the cytosolic leucine-rich repeat (LRR) domains. Importantly, mutational analysis demonstrates that a charged residue at the narrowest constriction of the homomeric channel is an important pore determinant of heteromeric VRAC. Additionally, a mutation in the flexible N-terminal portion of SWELL1 affects pore properties, suggesting a putative link between intracellular structures and channel regulation. This structure provides a scaffold for further dissecting the heterogeneity and mechanism of activation of VRAC., eLife digest Every cell needs to regulate its internal volume or it will burst. Most of a cell’s volume is a watery mixture of salts, proteins and other molecules. A cell can take in more water from its surroundings, diluting this mixture and causing the cell to expand. If a cell starts to take up too much water, it will open channel proteins in its outer membrane called volume regulated anion channels (or VRACs for short). An open VRAC allows negatively charged ions to leave the cell, and in the process causes water to leave the cell too. This relieves the pressure inside the cell, and the cell starts to shrink. The structure of a VRAC is thought to contain six subunits, and most include at least two different kinds of subunit. Some of the subunits must be a protein called SWELL1 (which is also known as LRRC8A). The other subunits can be any of four similar proteins from the same protein family. Since a VRAC can contain additional subunits drawing from this pool of five proteins, many structures are possible. But it remains unclear exactly how the structure of a VRAC allows it to sense and regulate the volume of a cell. This is partly because scientists do not have enough information about the architecture of this protein to understand how it might work. Using electron microscopes, Kefauver et al. have now captured detailed images of a VRAC composed entirely of human SWELL1 proteins. The overall structure of VRAC resembles a six-legged jellyfish, with a pore on the cell’s exterior passing through a constricted dome followed by three pairs of arms that extend into the cell’s interior. Given the observed structure, Kefauver et al. speculate that the arms of the SWELL1 proteins sense salt concentrations within the cell (to tell if its become diluted by an influx of water) and then interact with the rest of the channel. In response to these interactions, the domed part of the VRAC constricts or dilates to help regulate the cell’s volume. Molecular biologists can now use these structural details to further study the fundamentals behind how cells regulate their volume. This model will also improve scientific understanding of how diverse VRAC structures differ in their responses to changes in pressure within cells.

The EutL shell protein is a key component of the ethanolamine-utilization microcompartment, which serves to compartmentalize ethanolamine degradation in diverse bacteria. The apparent function of this shell protein is to facilitate the selective diffusion of large cofactor molecules between the cytoplasm and the lumen of the microcompartment. While EutL is implicated in molecular-transport phenomena, the details of its function, including the identity of its transport substrate, remain unknown. Here, the 2.1 Å resolution X-ray crystal structure of a EutL shell protein bound to cobalamin (vitamin B12) is presented and the potential relevance of the observed protein–ligand interaction is briefly discussed. This work represents the first structure of a bacterial microcompartment shell protein bound to a potentially relevant cofactor molecule.

BackgroundAcquired yellow hair (xanthotrichosis) can result from the deposition of pigmented compounds on the hair shaft or from chemical modification of hair pigment and protein molecules.PurposeA white-haired 77-year-old woman who developed xanthotrichosis of her scalp hair following the sequential application of bacitracin zinc ointment and selenium sulfide 2.5% lotion is described and the causes of yellow hair discoloration are reviewed.Materials and methodsThe clinical features of a woman with acquired yellow hair discoloration are presented. Using PubMed and Google Scholar, the following terms were searched and relevant citations were assessed: bacitracin zinc, hair discoloration, selenium sulfide, xanthotrichosis, and yellow hair.ResultsYellow hair was observed on the scalp in areas treated with the following regimen: prior to bedtime, several areas of the scalp were treated with a single application of bacitracin zinc ointment. The next morning, selenium sulfide 2.5% lotion was applied and then rinsed from the scalp during showering. Yellow hair discoloration was apparent in co-treated areas immediately following rinsing; the discoloration gradually faded over 2-5 days with regular shampooing.ConclusionsAcquired yellow hair shaft discoloration has been reported secondary to multiple etiologies, including environmental and occupational exposures, iatrogenic causes (including topical and systemic drugs) and protein-calorie malnutrition. To this list, we add yellow discoloration of white scalp hair due to application of selenium sulfide following topical use of bacitracin zinc in the affected areas as an unexpected adverse effect that may occur in individuals with white hair.

BackgroundAcquired yellow hair (xanthotrichosis) can result from the deposition of pigmented compounds on the hair shaft or from chemical modification of hair pigment and protein molecules. PurposeA white-haired 77-year-old woman who developed xanthotrichosis of her scalp hair following the sequential application of bacitracin zinc ointment and selenium sulfide 2.5% lotion is described and the causes of yellow hair discoloration are reviewed. Materials and methodsThe clinical features of a woman with acquired yellow hair discoloration are presented. Using PubMed and Google Scholar, the following terms were searched and relevant citations were assessed: bacitracin zinc, hair discoloration, selenium sulfide, xanthotrichosis, and yellow hair. ResultsYellow hair was observed on the scalp in areas treated with the following regimen: prior to bedtime, several areas of the scalp were treated with a single application of bacitracin zinc ointment. The next morning, selenium sulfide 2.5% lotion was applied and then rinsed from the scalp during showering. Yellow hair discoloration was apparent in co-treated areas immediately following rinsing; the discoloration gradually faded over 2-5 days with regular shampooing. ConclusionsAcquired yellow hair shaft discoloration has been reported secondary to multiple etiologies, including environmental and occupational exposures, iatrogenic causes (including topical and systemic drugs) and protein-calorie malnutrition. To this list, we add yellow discoloration of white scalp hair due to application of selenium sulfide following topical use of bacitracin zinc in the affected areas as an unexpected adverse effect that may occur in individuals with white hair.

Many bacteria conditionally express proteinaceous organelles referred to here as microcompartments (Fig. 1). These microcompartments are thought to be involved in a least seven different metabolic processes and the number is growing. Microcompartments are very large and structurally sophisticated. They are usually about 100–150 nm in cross section and consist of 10,000–20,000 polypeptides of 10–20 types. Their unifying feature is a solid shell constructed from proteins having bacterial microcompartment (BMC) domains. In the examples that have been studied, the microcompartment shell encases sequentially acting metabolic enzymes that catalyze a reaction sequence having a toxic or volatile intermediate product. It is thought that the shell of the microcompartment confines such intermediates, thereby enhancing metabolic efficiency and/or protecting cytoplasmic components. Mechanistically, however, this creates a paradox. How do microcompartments allow enzyme substrates, products and cofactors to pass while confining metabolic intermediates in the absence of a selectively permeable membrane? We suggest that the answer to this paradox may have broad implications with respect to our understanding of the fundamental properties of biological protein sheets including microcompartment shells, S-layers and viral capsids. BioEssays 30:1084–1095, 2008. © 2008 Wiley Periodicals, Inc.

Asparaginyl endopeptidase (AEP) is an endo/lysosomal cysteine endopeptidase with a preference for an asparagine residue at the P1 site and plays an important role in the maturation of toll-like receptors 3/7/9. AEP is known to undergo autoproteolytic maturation at acidic pH for catalytic activation. Here, we describe crystal structures of the AEP proenzyme and the mature forms of AEP. Structural comparisons between AEP and caspases revealed similarities in the composition of key residues and in the catalytic mechanism. Mutagenesis studies identified N44, R46, H150, E189, C191, S217/S218 and D233 as residues that are essential for the cleavage of the peptide substrate. During maturation, autoproteolytic cleavage of AEP's cap domain opens up access to the active site on the core domain. Unexpectedly, an intermediate autoproteolytic maturation stage was discovered at approximately pH 4.5 in which the partially activated AEP could be reversed back to its proenzyme form. This unique feature was confirmed by the crystal structure of AEPpH4.5 (AEP was matured at pH 4.5 and crystallized at pH 8.5), in which the broken peptide bonds were religated and the structure was transformed back to its proenzyme form. Additionally, the AEP inhibitor cystatin C could be digested by the fully activated AEP, but could not be digested by activated cathepsins. Thus, we demonstrate for the first time that cystatins may regulate the activity of AEP through substrate competition for the active site.

Bacterial microcompartments are a functionally diverse group of proteinaceous organelles that confine specific reaction pathways in the cell within a thin protein-based shell. The propanediol utilizing (Pdu) microcompartment contains the reactions for metabolizing 1,2-propanediol in certain enteric bacteria, including Salmonella. The Pdu shell is assembled from a few thousand protein subunits of several different types. Here we report the crystal structures of two key shell proteins, PduA and PduT. The crystal structures offer insights into the mechanisms of Pdu microcompartment assembly and molecular transport across the shell. PduA forms a symmetric homohexamer whose central pore appears tailored for facilitating transport of the 1,2-propanediol substrate. PduT is a novel, tandem domain shell protein that assembles as a pseudohexameric homotrimer. Its structure reveals an unexpected site for binding an [Fe-S] cluster at the center of the PduT pore. The location of a metal redox cofactor in the pore of a shell protein suggests a novel mechanism for either transferring redox equivalents across the shell or for regenerating luminal [Fe-S] clusters.

Hundreds of bacterial species produce proteinaceous microcompartments (MCPs) that act as simple organelles by confining the enzymes of metabolic pathways that have toxic or volatile intermediates. A fundamental unanswered question about bacterial MCPs is how enzymes are packaged within the protein shell that forms their outer surface. Here, we report that a short N-terminal peptide is necessary and sufficient for packaging enzymes into the lumen of an MCP involved in B 12 -dependent 1,2-propanediol utilization (Pdu MCP). Deletion of 10 or 14 amino acids from the N terminus of the propionaldehyde dehydrogenase (PduP) enzyme, which is normally found within the Pdu MCP, substantially impaired packaging, with minimal effects on its enzymatic activity. Fusion of the 18 N-terminal amino acids from PduP to GFP, GST, or maltose-binding protein resulted in their encapsulation within MCPs. Bioinformatic analyses revealed N-terminal extensions in two additional Pdu proteins and three proteins from two unrelated MCPs, suggesting that N-terminal peptides may be used to package proteins into diverse MCPs. The potential uses of MCP assembly principles in nature and in biotechnology are discussed.

Some bacteria contain organelles or microcompartments consisting of a large virion-like protein shell encapsulating sequentially acting enzymes. These organized microcompartments serve to enhance or protect key metabolic pathways inside the cell. The variety of bacterial microcompartments provide diverse metabolic functions, ranging from CO2 fixation to the degradation of small organic molecules. Yet they share an evolutionarily related shell, which is defined by a conserved protein domain that is widely distributed across the bacterial kingdom. Structural studies on a number of these bacterial microcompartment shell proteins are illuminating the architecture of the shell and highlighting its critical role in controlling molecular transport into and out of microcompartments. Current structural, evolutionary, and mechanistic ideas are discussed, along with genomic studies for exploring the function and diversity of this family of bacterial organelles.

Bacterial microcompartments (BMCs) are large intracellular bodies that serve as simple organelles in many bacteria. They are proteinaceous structures composed of key enzymes encapsulated by a polyhedral protein shell. In previous studies, the organization of these large shells has been inferred from the conserved packing of the component shell proteins in two-dimensional (2D) layers within the context of three-dimensional (3D) crystals. Here, we show that well-ordered, 2D crystals of carboxysome shell proteins assemble spontaneously when His-tagged proteins bind to a monolayer of nickelated lipid molecules at an air-water interface. The molecular packing within the 2D crystals recapitulates the layered hexagonal sheets observed in 3D crystals. The results reinforce current models for the molecular design of BMC shells.

Previous studies of symmetry preferences in protein crystals suggest that symmetric proteins, such as homodimers, might crystallize more readily on average than asymmetric, monomeric proteins. Proteins that are naturally monomeric can be made homodimeric artificially by forming disulfide bonds between individual cysteine residues introduced by mutagenesis. Furthermore, by creating a variety of single-cysteine mutants, a series of distinct synthetic dimers can be generated for a given protein of interest, with each expected to gain advantage from its added symmetry and to exhibit a crystallization behavior distinct from the other constructs. This strategy was tested on phage T4 lysozyme, a protein whose crystallization as a monomer has been studied exhaustively. Experiments on three single-cysteine mutants, each prepared in dimeric form, yielded numerous novel crystal forms that cannot be realized by monomeric lysozyme. Six new crystal forms have been characterized. The results suggest that synthetic symmetrization may be a useful approach for enlarging the search space for crystallizing proteins.

Summary The Pdu microcompartment is a proteinaceous, subcellular structure that serves as an organelle for the metabolism of 1,2-propanediol in Salmonella enterica . It encapsulates several related enzymes within a shell composed of a few thousand protein subunits. Recent structural studies on the carboxysome, a related microcompartment involved in CO 2 fixation, have concluded that the major shell proteins from that microcompartment form hexamers that pack into layers comprising the facets of the shell. Here we report the crystal structure of PduU, a protein from the Pdu microcompartment, representing the first structure of a shell protein from a noncarboxysome microcompartment. Though PduU is a hexamer like other characterized shell proteins, it has undergone a circular permutation leading to dramatic differences in the hexamer pore. In view of the hypothesis that microcompartment metabolites diffuse across the outer shell through these pores, the unique structure of PduU suggests the possibility of a special functional role.