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Volume 271, Number 34, Issue of August 23, 1996 pp. 20845-20852
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Cytoplasmic O-GlcNAc Modification of the Head Domain and the KSP Repeat Motif of the Neurofilament Protein Neurofilament-H

(Received for publication, April 19, 1996, and in revised form, May 31, 1996)

Dennis L.-Y. Dong , Zuo-Shang Xu , Gerald W. Hart and Don W. Cleveland ^''

From the Departments of  Biological Chemistry and ^'' Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, the  Department of Biochemistry and Molecular Genetics, Schools of Medicine/Dentistry, University of Alabama, Birmingham, Alabama 35294, and the  Ludwig Institute for Cancer Research and the Departments of Medicine and Neuroscience, University of California at San Diego, La Jolla, California 92093

Neurofilaments, the major intermediate filaments in large myelinated neurons, are essential for specifying proper axonal caliber. Mammalian neurofilaments are obligate heteropolymers assembled from three polypeptides, neurofilament (NF)-H, NF-M, and NF-L, each of which undergoes phosphorylation at multiple sites. NF-M and NF-L are known to be modified by O-linked N-acetylglucosamine (O-GlcNAc) (Dong, D. L.-Y., Xu, Z.-S., Chevrier, M. R., Cotter, R. J., Cleveland, D. W., and Hart, G. W. (1993) J. Biol. Chem. 268, 16679-16687). Here we further report that NF-H is extensively modified by O-GlcNAc at Thr⁵³, Ser⁵⁴, and Ser⁵⁶ in the head domain and, somewhat surprisingly, at multiple sites within the Lys-Ser-Pro repeat motif in the tail domain, a region in assembled neurofilaments known to be nearly stoichiometrically phosphorylated on each of the ~50 KSP repeats. Beyond the earlier identified sites on NF-M and NF-L, O-GlcNAc sites on Thr¹⁹ and Ser³⁴ of NF-M and Ser³⁴ and Ser⁴⁸ of NF-L are also determined here, all of which are localized in head domain sequences critical for filament assembly. The proximity of O-GlcNAc and phosphorylation sites in both head and tail domains of each subunit indicates that these modifications may influence one another and play a role in filament assembly and network formation.

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