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Fig. 16. LL4, (L1487L1488), mediates internalization of MNK. Although a small amount of protein is constituitively recycling between the TGN and plasma membrane, the protein expressed from the full-length cDNA (MNKMYC) is primarily resident at the TGN (A, B). However, after 40 h, there is a gradual accumulation of MNKMYCALL4 (C, D). This results from the inability of this mutant to internalize and is evidence that L1487L1488 is functional in MNK (31).

Fig. 17. Copper-induced relocalization of MNK. MNK is primarily resident at the TGN, retained by a signal within TM3. Copper binds to the N-terminal copper-binding domains, which may bring about a structural change within the protein, reducing the retentive qualities of TM3. MNK trafficks to the plasma membrane where it effluxes copper from the cell. On the removal of copper, MNK returns to the TGN via the recycling endosome, utilizing the dileucine motif (L1487L1488) at the C-terminus of the protein.

Fig. 17. Copper-induced relocalization of MNK. MNK is primarily resident at the TGN, retained by a signal within TM3. Copper binds to the N-terminal copper-binding domains, which may bring about a structural change within the protein, reducing the retentive qualities of TM3. MNK trafficks to the plasma membrane where it effluxes copper from the cell. On the removal of copper, MNK returns to the TGN via the recycling endosome, utilizing the dileucine motif (L1487L1488) at the C-terminus of the protein.

TGN, and, third, further unidentified motif(s) are required to sort the protein from the early/recycling endosomes to the TGN.

In conjunction with similar studies into the function and trafficking of WND, it will be important to build on these results and determine the similarity of both proteins in their functional properties. Depending on the outcome of these results, a suitable approach to therapy for Menkes disease may involve the upregulation or induction of expression of WND in tissues normally expressing MNK.

Menkes disease has become of great interest to researchers interested in the exocytic and endocytic trafficking of the cell and those investigating the mechansims behind copper homeostasis. Further studies will help to elucidate the mechanisms involved in this trafficking and, most importantly of all, may lead to novel therapies with which this fatal neurodegenerative disorder can be successfully treated.

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