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 the 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 Fbx16, was found to associate with the C-terminal acidic region of L-periaxin, in a search for binding partners of L-periaxin using the yeast two-hybrid. 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 (Skp1/Cullin1/F-box), which is responsible for the recruitment of substrates for ubiquitination and subsequent destruction. Fbx16 belongs to the leucine-rich 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-dystrophin related protein 2 (DRP2) complex, suggests an indirect role for Fbx16 in the structural and signalling functions of the cortical cytoskeleton. Regulation of the levels of L-periaxin by the ubiquitin/proteasome pathway, mediated by Fbx16, is likely to be important for the stabilisation of the Schwann cell - axon unit.