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Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor

Colleen A McGourty1, David Akopian2, Carolyn Walsh1

  • 1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

Cell
|October 8, 2016
PubMed

Insights

The study reveals how calcium signals activate the CUL3 ubiquitin ligase complex via PEF1 and ALG2 co-adaptors. This process regulates collagen secretion and craniofacial bone development.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Developmental Biology

Background:

  • The ubiquitin ligase CUL3 (Cullin 3) is crucial for neural crest development and implicated in diseases like autism and schizophrenia.
  • CUL3 functions through numerous substrate adaptors, but their activation mechanisms remain largely unknown.

Purpose of the Study:

  • To elucidate the activation mechanism of the CUL3-KLHL12 complex in regulating substrate ubiquitylation.
  • To understand the role of calcium signaling in CUL3-mediated ubiquitylation and its impact on collagen secretion and development.

Main Methods:

  • Investigated the interaction between CUL3, KLHL12, PEF1, ALG2, and SEC31 using biochemical assays.
  • Analyzed the effect of calcium levels on SEC31 ubiquitylation and COPII coat formation.
  • Examined the role of this pathway in chondrocyte differentiation and craniofacial bone formation.

Main Results:

  • PEF1 and ALG2 act as calcium-dependent co-adaptors for the CUL3-KLHL12 complex, specifically recognizing the substrate SEC31.
  • Calcium signaling enhances SEC31 ubiquitylation, leading to the formation of large COPII coats and increased collagen secretion.
  • The calcium-dependent CUL3-KLHL12 pathway integrates collagen secretion into chondrocyte differentiation and craniofacial bone development.

Conclusions:

  • Calcium-binding proteins PEF1 and ALG2 mediate the activation of the CUL3-KLHL12 ubiquitin ligase complex in response to calcium signals.
  • This calcium-dependent ubiquitylation pathway is essential for regulating collagen secretion and plays a significant role in craniofacial bone formation.
  • The findings identify CUL3 co-adaptors and calcium as key regulators of ubiquitylation events critical for human development.
Keywords:
CUL3SEC31calciumendoplasmic reticulumubiquitin

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