The second group of residues includes those located at the interfacial helices between the N-lobe and the C-lobe, i.e. N519, A524, F528, G708, and M712. Since the interlobar cleft is the site of ATP and carbohydrate binding as well as where phosphoryl transfer occurs, mutation of these residues could change the interlobar movement during catalysis and thus affect the kinase activity of the protein. For example, the first identified HIBM-related mutation, M712T [13] , would likely abolish the hydrophobic interaction of the side chain of M712 with that of L523 from the C-lobe helix (Figure 8a ). In the previous study [11] , the M712T mutation has been shown to cause a 30% reduction in the kinase activity without affecting the epimerase activity of full length GNE. On the contrary, mutations of other residues in this second group reduce not only the kinase activity but also the epimerase activity of the full length protein ( [11] , Table 1 ). This suggests that the kinase domain is allosterically coupled to the epimerase domain. The structure of the full length GNE is needed to fully understand the coupled effects of the kinase and epimerase domains.