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N-acetyl-D-glucosamine kinase binds dynein light chain roadblock 1 and promotes protein aggregate clearance.

ABSTRACT: Emerging evidence indicates that neurodegenerative diseases (NDs) result from a failure to clear toxic protein aggregates rather than from their generation. We previously showed N-acetylglucosamine kinase (NAGK) promotes dynein functionality and suggested this might promote aggregate removal and effectively address proteinopathies. Here, we report NAGK interacts with dynein light chain roadblock type 1 (DYNLRB1) and efficiently suppresses mutant huntingtin (mHtt) (Q74) and ?-synuclein (?-syn) A53T aggregation in mouse brain cells. A kinase-inactive NAGKD107A also efficiently cleared Q74 aggregates. Yeast two-hybrid selection and in silico protein-protein docking analysis showed the small domain of NAGK (NAGK-DS) binds to the C-terminal of DYNLRB1. Furthermore, a small peptide derived from NAGK-DS interfered with Q74 clearance. We propose binding of NAGK-DS to DYNLRB1 'pushes up' the tail of dynein light chain and confers momentum for inactive phi- to active open-dynein transition.

SUBMITTER: Ripon MKH 

PROVIDER: S-EPMC7427805 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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N-acetyl-D-glucosamine kinase binds dynein light chain roadblock 1 and promotes protein aggregate clearance.

Ripon Md Kamal Hossain MKH   Lee HyunSook H   Dash Raju R   Choi Ho Jin HJ   Oktaviani Diyah Fatimah DF   Moon Il Soo IS   Haque Md Nazmul MN  

Cell death & disease 20200814 8

Emerging evidence indicates that neurodegenerative diseases (NDs) result from a failure to clear toxic protein aggregates rather than from their generation. We previously showed N-acetylglucosamine kinase (NAGK) promotes dynein functionality and suggested this might promote aggregate removal and effectively address proteinopathies. Here, we report NAGK interacts with dynein light chain roadblock type 1 (DYNLRB1) and efficiently suppresses mutant huntingtin (mHtt) (Q74) and α-synuclein (α-syn) A5  ...[more]

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