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      Crystal Structure of the N-Acetylmannosamine Kinase Domain of GNE


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          UDP-GlcNAc 2-epimerase/ManNAc 6-kinase, GNE, is a bi-functional enzyme that plays a key role in sialic acid biosynthesis. Mutations of the GNE protein cause sialurea or autosomal recessive inclusion body myopathy/Nonaka myopathy. GNE is the only human protein that contains a kinase domain belonging to the ROK (repressor, ORF, kinase) family.

          Principal Findings

          We solved the structure of the GNE kinase domain in the ligand-free state. The protein exists predominantly as a dimer in solution, with small populations of monomer and higher-order oligomer in equilibrium with the dimer. Crystal packing analysis reveals the existence of a crystallographic hexamer, and that the kinase domain dimerizes through the C-lobe subdomain. Mapping of disease-related missense mutations onto the kinase domain structure revealed that the mutation sites could be classified into four different groups based on the location – dimer interface, interlobar helices, protein surface, or within other secondary structural elements.


          The crystal structure of the kinase domain of GNE provides a structural basis for understanding disease-causing mutations and a model of hexameric wild type full length enzyme.

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          Most cited references25

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          Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective.

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            The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy.

            Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.
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              SOLVE and RESOLVE: automated structure solution and density modification.

              SOLVE and RESOLVE have shown that it is possible to automate a significant part of the macromolecular X-ray structure determination process. The key elements of seamless and compatible subprograms, scoring algorithms, and error-tolerant software systems have been important in implementing these programs. The principles used in SOLVE and RESOLVE can be applied to other aspects of structure determination as well, suggesting that full automation of the entire structure determination process from scaling diffraction data to a refined model will be possible in the near future.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                20 October 2009
                : 4
                : 10
                : e7165
                [1 ]Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
                [2 ]Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
                University of Cambridge, United Kingdom
                Author notes

                Conceived and designed the experiments: YT HWP. Performed the experiments: YT WT LN FM. Analyzed the data: YT WT. Wrote the paper: YT WT HWP.

                Tong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                : 4 June 2009
                : 1 September 2009
                Page count
                Pages: 9
                Research Article
                Biochemistry/Structural Genomics
                Pathology/Molecular Pathology



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