Class I hydrophobins are a unique family of fungal proteins that form a polymeric, water-repellent monolayer on the surface of structures such as spores and fruiting bodies. Similar monolayers are being discovered on an increasing range of important microorganisms. Hydrophobin monolayers are amphipathic and particularly robust, and they reverse the wettability of the surface on which they are formed. There are also significant similarities between these polymers and amyloid-like fibrils. However, structural information on these proteins and the rodlets they form has been elusive. Here, we describe the three-dimensional structure of the monomeric form of the class I hydrophobin EAS. EAS forms a -barrel structure punctuated by several disordered regions and displays a complete segregation of charged and hydrophobic residues on its surface. This structure is consistent with its ability to form an amphipathic polymer. By using this structure, together with data from mutagenesis and previous biophysical studies, we have been able to propose a model for the polymeric rodlet structure adopted by these proteins. X-ray fiber diffraction data from EAS rodlets are consistent with our model. Our data provide molecular insight into the nature of hydrophobin rodlet films and extend our understanding of the fibrillar -structures that continue to be discovered in the protein world. amyloid ͉ NMR ͉ polymer H ydrophobins are a large family of secreted, low-molecularmass (7-9 kDa) proteins unique to filamentous fungi. There is little amino acid sequence similarity between hydrophobins, except for a characteristic pattern of eight cysteine residues that form four intramolecular disulfide bonds (1, 2). These proteins have remarkable biophysical properties and function by selfassembling into amphipathic polymeric films at the interface between hydrophobic and hydrophilic surfaces (3). The surfactive and amphipathic properties of hydrophobins facilitate the formation of essential aerial structures such as hyphae, spores, and fruiting bodies (4).Two classes of hydrophobins have been identified based on their hydrophobicity plots and physical properties (5). For class I hydrophobins, the polymer film comprises cylindrical rodlets with dimensions of Ϸ10 ϫ 100-250 nm and their outward-facing hydrophobic surface has extremely low wettability (6, 7). These films are very robust; they are resistant to boiling in detergents or strong alkalis (8, 9). The morphology of isolated rodlets is reminiscent of amyloid fibrils isolated from diseased tissue and formed in vitro. Reconstituted rodlets stained with Congo red give the green-gold birefringence characteristic of similarly stained amyloid fibers and circular dichroism (CD) data indicate that the rodlets contain extensive -structure, suggesting that rodlets and amyloid fibrils have structural features in common (10, 11, **). Class II hydrophobin films are significantly less robust and lack the rodlet morphology of class I hydrophobins (12, 13).Class I hydrophobins, once solubilized, will spo...
EAS joins an increasing number of proteins that undergo a disorder-->order transition in carrying out their normal function. This report is one of the few examples where an amyloid-like state represents the wild-type functional form. Thus the mechanism of amyloid formation, now thought to be a general property of polypeptide chains, has actually been applied in nature to form these remarkable structures.
Acetaminophen (APAP)-induced acute liver failure (ALF) remains a major clinical problem. Although a majority of patients recovers after severe liver injury, a subpopulation of patients proceeds to ALF. Bile acids are generated in the liver and accumulate in blood during liver injury, and as such, have been proposed as biomarkers for liver injury and dysfunction. The goal of this study was to determine whether individual bile acid levels could determine outcome in patients with APAP-induced ALF (AALF). Serum bile acid levels were measured in AALF patients using mass spectrometry. Bile acid levels were elevated 5-80-fold above control values in injured patients on day 1 after the overdose and decreased over the course of hospital stay. Interestingly, glycodeoxycholic acid (GDCA) was significantly increased in non-surviving AALF patients compared with survivors. GDCA values obtained at peak alanine aminotransferase (ALT) and from day 1 of admission indicated GDCA could predict survival in these patients by receiver-operating characteristic analysis (AUC = 0.70 for day 1, AUC = 0.68 for peak ALT). Of note, AALF patients also had significantly higher levels of serum bile acids than patients with active cholestatic liver injury. These data suggest measurements of GDCA in this patient cohort modestly predicted outcome and may serve as a prognostic biomarker. Furthermore, accumulation of bile acids in serum or plasma may be a result of liver cell dysfunction and not cholestasis, suggesting elevation of circulating bile acid levels may be a consequence and not a cause of liver injury.
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