Allosteric control of Ubp6 and the proteasome via a bidirectional switch.

The proteasome recognizes ubiquitinated proteins and can also edit ubiquitin marks, allowing substrates to be rejected based on ubiquitin chain topology. In yeast, editing is mediated by deubiquitinating enzyme Ubp6. The proteasome activates Ubp6, whereas Ubp6 inhibits the proteasome through deubiquitination and a noncatalytic effect. Here, we report cryo-EM structures of the proteasome bound to Ubp6, based on which we identify mutants in Ubp6 and proteasome subunit Rpt1 that abrogate Ubp6 activation. The Ubp6 mutations define a conserved region that we term the ILR element. The ILR is found within the BL1 loop, which obstructs the catalytic groove in free Ubp6. Rpt1-ILR interaction opens the groove by rearranging not only BL1 but also a previously undescribed network of three interconnected active-site-blocking loops. Ubp6 activation and noncatalytic proteasome inhibition are linked in that they are eliminated by the same mutations. Ubp6 and ubiquitin together drive proteasomes into a unique conformation associated with proteasome inhibition. Thus, a multicomponent allosteric switch exerts simultaneous control over both Ubp6 and the proteasome.

Atomic structures of an entire contractile injection system in both the extended and contracted states.

Contractile injection systems are sophisticated multiprotein nanomachines that puncture target cell membranes. Although the number of atomic-resolution insights into contractile bacteriophage tails, bacterial type six secretion systems and R-pyocins is rapidly increasing, structural information on the contraction of bacterial phage-like protein-translocation structures directed towards eukaryotic hosts is scarce. Here, we characterize the antifeeding prophage AFP from Serratia entomophila by cryo-electron microscopy. We present the high-resolution structure of the entire AFP particle in the extended state, trace 11 protein chains de novo from the apical cap to the needle tip, describe localization variants and perform specific structural comparisons with related systems. We analyse inter-subunit interactions and highlight their universal conservation within contractile injection systems while revealing the specificities of AFP. Furthermore, we provide the structure of the AFP sheath-baseplate complex in a contracted state. This study reveals atomic details of interaction networks that accompany and define the contraction mechanism of toxin-delivery tailocins, offering a comprehensive framework for understanding their mode of action and for their possible adaptation as biocontrol agents.

Spinal schistosomiasis: differential diagnosis for acute paraparesis in a U.S. resident.

BACKGROUND: Spinal schistosomiasis is a severe presentation of Schistosoma mansoni infection, which is endemic in South America, the Middle East, and sub-Saharan Africa. With increasing international travel, a disease can spread from an endemic area to another part of the world easily. OBJECTIVES: To present a case of a US resident who developed acute paraparesis due to spinal schistosomiasis after traveling to sub-Saharan Africa. PARTICIPANT: A 45-year-old woman presented with abdominal pain radiating into the bilateral lower extremities. She was diagnosed with a pelvic mass and underwent an urgent hysterectomy with right salpingo-oopherectomy. Postoperatively, she developed progressive weakness with worsening pain in her bilateral lower extremities and neurogenic bladder. Magnetic resonance imaging showed an abnormal T2 hyperintense signal in the entire spinal cord below the T3 level with abnormal contrast enhancement from T9 through the conus medullaris. Spinal fluid analysis showed lymphocytic pleocytosis and elevated protein. The patient was diagnosed with transverse myelitis. Subsequently, a detailed history revealed a visit to Ethiopia 2 years earlier. Tests for S mansoni were positive. After treatment with praziquantel and prednisone, her neurologic function began to improve. CONCLUSIONS: An increasing incidence of international travel is increasing the likelihood of US physicians' encountering this treatable condition. Travelers with spinal schistosomiasis may not have symptoms of systemic infection. Therefore, it is important to include spinal schistosomiasis in the differential diagnosis of acute inflammatory myelopathy, particularly with a history of travel to endemic areas.