Many disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins, but the molecular mechanism of their pathogenicity is enigmatic. Here, we employ a peptide-based proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1, and CACNA1H) lead to an increased clathrin binding. All three mutations create dileucine motifs known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking down AP-2 reverts the cellular mislocalization and restores glucose transport. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in structurally disordered cytosolic domains of transmembrane proteins. Thus, several mutations in disordered regions appear to cause "dileucineopathies."

Chromospheric evaporation refers to dynamic mass motions in flare loops as a result of rapid energy deposition in the chromosphere. These have been observed as blueshifts in X-ray and extreme-ultraviolet (EUV) spectral lines corresponding to upward motions at a few tens to a few hundreds of km s −1 . Past spectroscopic observations have also revealed a dominant stationary component, in addition to the blueshifted component, in emission lines formed at high temperatures (∼10 MK). This is contradictory to evaporation models predicting predominant blueshifts in hot lines. The recently launched Interface Region Imaging Spectrograph (IRIS) provides high resolution imaging and spectroscopic observations that focus on the chromosphere and transition region in the UV passband. Using the new IRIS observations, combined with coordinated observations from the EUV Imaging Spectrometer, we study the chromospheric evaporation process from the upper chromosphere to corona during an X1.0 flare on 2014 March 29. We find evident evaporation signatures, characterized by Doppler shifts and line broadening, at two flare ribbons separating from each other, suggesting that chromospheric evaporation takes place in successively formed flaring loops throughout the flare. More importantly, we detect dominant blueshifts in the high temperature Fe xxi line (∼10 MK), in agreement with theoretical predictions. We also find that, in this flare, gentle evaporation occurs at some locations in the rise phase of the flare, while explosive evaporation is detected at some other locations near the peak of the flare. There is a conversion from gentle to explosive evaporation as the flare evolves.-2 -

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It is well known that two-ribbon flares observed in Hα and ultraviolet (UV) wavelengths mostly exhibit compact and localized hard X-ray (HXR) sources (Warren & Warshall 2001). In this paper, we present comprehensive analysis of a two-ribbon flare observed in UV 1600Å by TRACE and in HXRs by RHESSI. HXR (25 -100 keV) imaging observations show two kernels of size (FWHM) 15 ′′ moving along the two UV ribbons. We find the following results. (1) UV brightening is substantially enhanced wherever and whenever the compact HXR kernel is passing, and during the hard X-ray transit across a certain region, the UV counts light curve in that region is temporally correlated with the hard X-ray total flux light curve. After the passage of the HXR kernel, the UV light curve exhibits smooth monotonical decay. (2) We measure the apparent motion speed of the HXR sources and UV ribbon fronts, and decompose the motion into parallel and perpendicular motions with respect to the magnetic polarity inversion line (PIL). It is found that HXR kernels and UV fronts exhibit similar apparent motion patterns and speeds. The parallel motion dominates during the rise of the HXR emission, and the perpendicular motion starts and dominates at the HXR peak, the apparent motion speed being 10 -40 km s −1 .(3) We also find that UV emission is characterized by a rapid rise correlated with HXRs, followed by a long decay on timescales of 15 -30 min. The above analysis provides evidence that UV brightening is primarily caused by beam heating, which also produces thicktarget HXR emission. The thermal origin of UV emission cannot be excluded, but would produce weaker heating by one order of magnitude. The extended UV ribbons in this event are most likely a result of sequential reconnection along the PIL, which produces individual flux tubes (post-flare loops), subsequent nonthermal energy release and heating in these flux tubes, and then the very long cooling time of the transition region at the feet of these flux tubes.

Staphylococcus aureus secretes a phosphatidylinositol-specific phospholipase C (PIPLC) as a virulence factor that is unusual in exhibiting higher activity at acidic pH values than other enzymes in this class. We have determined the crystal structure of this enzyme at pH 4.6 and pH 7.5. Under slightly basic conditions, the S. aureus PI-PLC structure closely follows the conformation of other bacterial PI-PLCs. However, when crystallized under acidic conditions, a large section of mobile loop at the αβ-barrel rim in the vicinity of the active site shows ~10 Å shift. This loop displacement at acidic pH is the result of a titratable intramolecular π-cation interaction between His258 and Phe249. This was verified by a structure of the mutant protein H258Y crystallized at pH 4.6, which does not exhibit the large loop shift. The intramolecular π-cation interaction for S. aureus PI-PLC provides an explanation for the activity of the enzyme at acid pH and also suggests how phosphatidylcholine, as a competitor for Phe249, may kinetically activate this enzyme.