A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

HSP27 is a human molecular chaperone that forms large, dynamic oligomers and functions in many aspects of cellular homeostasis. Mutations in HSP27 cause Charcot‐Marie‐Tooth (CMT) disease, the most common inherited disorder of the peripheral nervous system. A particularly severe form of CMT disease is triggered by the P182L mutation in the highly conserved IxI/V motif of the disordered C‐terminal region, which interacts weakly with the structured core domain of HSP27. Here, we observed that the P182L mutation disrupts the chaperone activity and significantly increases the size of HSP27 oligomers formed in vivo, including in motor neurons differentiated from CMT patient‐derived stem cells. Using NMR spectroscopy, we determined that the P182L mutation decreases the affinity of the HSP27 IxI/V motif for its own core domain, leaving this binding site more accessible for other IxI/V‐containing proteins. We identified multiple IxI/V‐bearing proteins that bind with higher affinity to the P182L variant due to the increased availability of the IxI/V‐binding site. Our results provide a mechanistic basis for the impact of the P182L mutation on HSP27 and suggest that the IxI/V motif plays an important, regulatory role in modulating protein–protein interactions.     

Syngamosis,an unusual cause of asthma: the first reported case in Canada.

The first case of syngamosis in a human in Canada is reported. The patient, a traveller to the Caribbean islands, presented with a chronic dry cough. The nematode Syngamus laryngeus is found in wild and domestic birds and mammals in the tropics and subtropics. Humans are only accidental hosts. The diagnosis of syngamosis is usually made by fibreoptic bronchoscopic examination, which reveals the Y-shaped worms in the bronchi or the characteristic eggs in the sputum or feces. Physicians must be alerted to the possibility of syngamosis in patients with symptoms of asthma who have recently travelled to South America or the Caribbean islands.