14‐3‐3η is a novel regulator of parkin ubiquitin ligase

Shigeto Sato, Tomoki Chiba, Eri Sakata, Koichi Kato, Yoshikuni Mizuno, Nobutaka Hattori, Keiji Tanaka

Author Affiliations

  1. Shigeto Sato1,2,
  2. Tomoki Chiba2,
  3. Eri Sakata3,
  4. Koichi Kato3,
  5. Yoshikuni Mizuno1,
  6. Nobutaka Hattori1 and
  7. Keiji Tanaka*,2
  1. 1 Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan
  2. 2 Tokyo Metropolitan Institute of Medical Science, Bunkyo‐ku Tokyo, Japan
  3. 3 Department of Structural Biology and Biomolecular Engineering, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho‐ku, Nagoya, Japan
  1. *Corresponding author. Department of Molecular Oncology, The Tokyo Metropolitan Institute of Medical Science, 3‐18‐22 Honkomagome, Bunkyo‐ku, Tokyo 113‐8613, Japan. Tel./Fax: +81 3 3823 2237; E‐mail: tanakak{at}
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Mutation of the parkin gene, which encodes an E3 ubiquitin‐protein ligase, is the major cause of autosomal recessive juvenile parkinsonism (ARJP). Although various substrates for parkin have been identified, the mechanisms that regulate the ubiquitin ligase activity of parkin are poorly understood. Here we report that 14‐3‐3η, a chaperone‐like protein present abundantly in neurons, could bind to parkin and negatively regulate its ubiquitin ligase activity. Furthermore, 14‐3‐3η could bind to the linker region of parkin but not parkin with ARJP‐causing R42P, K161N, and T240R mutations. Intriguingly, α‐synuclein (α‐SN), another familial Parkinson's disease (PD) gene product, abrogated the 14‐3‐3η‐induced suppression of parkin activity. α‐SN could bind tightly to 14‐3‐3η and consequently sequester it from the parkin–14‐3‐3η complex. PD‐causing A30P and A53T mutants of α‐SN could not bind 14‐3‐3η, and failed to activate parkin. Our findings indicate that 14‐3‐3η is a regulator that functionally links parkin and α‐SN. The α‐SN‐positive and 14‐3‐3η‐negative control of parkin activity sheds new light on the pathophysiological roles of parkin.

  • Received January 24, 2005.
  • Accepted July 15, 2005.
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