Direct binding of the flexible C-terminal segment of periaxin to β4 integrin suggests a molecular basis for CMT4F

Abstract

The process of myelination in the nervous system requires coordinated formation of both transient and stable supramolecular complexes. Myelin-specific proteins play key roles in these assemblies, which may link membranes to each other or connect the myelinating cell cytoskeleton to the extracellular matrix. The myelin protein periaxin is known to play an important role in linking the Schwann cell cytoskeleton to the basal lamina through membrane receptors, such as the dystroglycan complex. Mutations that truncate periaxin from the C terminus cause demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 4F, indicating a function for the periaxin C-terminal region in myelination. We identified the cytoplasmic domain of β4 integrin as a specific high-affinity binding partner for periaxin. The C-terminal region of periaxin remains unfolded and flexible when bound to the third fibronectin type III domain of β4 integrin. Our data suggest that periaxin is able to link the Schwann cell cytoplasm to the basal lamina through a two-pronged interaction via different membrane protein complexes, which bind close to the N and C terminus of this elongated, flexible molecule.

Integrin α6β4 Recognition of a Linear Motif of Bullous Pemphigoid Antigen BP230 Controls Its Recruitment to Hemidesmosomes

“…The region FnIII-3,4-C-tail also interacts with Solo (ARHGEF40), a guanine nucleotide exchange factor of the RhoA small guanosine triphosphatase, for the formation of HDs in mammary epithelial cells (Fujiwara et al, 2018). Recently, binding of the FnIII-3 domain to L-periaxin, a myelin protein of Schwann cells, has been described (Raasakka et al, 2019).…”

Direct Binding of the Flexible C-Terminal Segment of Periaxin to β4 Integrin Suggests a Molecular Basis for CMT4F

“…We are grateful to NanoTemper Technologies GmbH and Dr Teresia Hallström for providing access to nanoDSF instrumentation. This manuscript has been released as a pre-print at bioRxiv (Raasakka et al, 2019b).…”