The morphological changes required for the ensheathment of peripheral nerve
axons by Schwann cells are believed to be regulated by the cell cytoskeleton and its
associated proteins. Control of the levels of these proteins is likely to be necessary for
the assembly of compact myelin and the stability of the sheath.
L-periaxin was initially identified as a putative cytoskeleton-associated protein
expressed by myelin-forming Schwann cells based upon its insolubility in non-ionic
detergent. The pattern of developmental expression of L-periaxin and its shift in
localisation from the adaxonal to abaxonal membranes of myelinating Schwann cells
following their association with axons, implied a role in the stabilisation of the myelin
sheath. In this work, an F-box containing protein termed Fbxl6, was found to associate
with the C-terminal acidic region of L-periaxin, in a search for binding partners of Lperiaxin
using the yeast two-hybrid method. The observed interaction was verified by
in vitro pull down assays using mouse sciatic nerve homogenate and L-periaxin
generated by in vitro transcription/ translation.
F-box proteins have been identified as components of a multi-enzyme complex
termed SCF (Skp 1 / Cullin 1/F-box), which is responsible for the recruitment of
substrates for ubiquitination and subsequent destruction. Fbxl6 belongs to the leucinerich
repeat (LRR)-containing subfamily of F-box proteins. The C-terminal LRR region
of the protein serves as the binding site for L-periaxin. whereas the F-box motif permits
association with the core SCF complex. L-periaxin was detected as a ubiquitin
conjugate in sciatic nerve explant cultures. Ubiquitination of the protein acts as a signal
for degradation by the 26S proteasome, as revealed by stabilisation of L-periaxin upon
inhibition of the proteasome by epoxomicin.
The participation of L-periaxin in a recently identified dystroglycan- dystrophinrelated
protein 2 (DRP2) complex, suggests an indirect role for Fbxl6 in the structural
and signalling functions of the cortical cytoskeleton. Regulation of the levels of Lperiaxin
by the ubiquitin/ proteasome pathway, mediated by Fbxl6, is likely to be
important for the stabilisation of the Schwann cell-axon unit.