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Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode

Zhenyi Zhang1, Senem Akyildiz2, Yafei Xiao1

  • 1School of Life Sciences and Biotechnology, State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University , Shanghai, China.

Cell Discovery
|July 28, 2016
PubMed

Insights

The tumor suppressor APC recognizes binding partners like Amer1/WTX through its armadillo repeat (ARM) domain. This study reveals a consensus recognition pattern for APC-ARM interactions, crucial for Wnt signaling and cell adhesion.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cell Biology

Background:

  • The Adenomatous Polyposis Coli (APC) tumor suppressor protein interacts with numerous partners via its armadillo repeat (ARM) domain.
  • Amer1/WTX is a key APC-binding protein implicated in Wilms' tumor and bone overgrowth syndrome, regulating Wnt signaling and cell adhesion.

Purpose of the Study:

  • To elucidate the structural basis of APC-ARM domain recognition of Amer1/WTX and other binding partners.
  • To identify novel interaction sites and characterize the binding mechanisms.

Main Methods:

  • X-ray crystallography to determine the structures of APC-ARM in complex with Amer1 peptides (A1, A2, A4).
  • Biochemical assays including GST pull-down, yeast two-hybrid, and isothermal titration calorimetry (ITC) using mutant proteins.
  • Cell-based assays to assess the functional consequences of disrupting APC-Amer1 interactions.

Main Results:

  • Crystal structures revealed how Amer1 peptides A1, A2, and a newly identified A4 interact with APC-ARM.
  • A common recognition pattern was identified for Amer1-A1, -A2, -A4, and other APC-ARM binding proteins (Asef, Sam68).
  • Amer1-A3 binds APC-ARM via a distinct bipartite mode at the C-terminal side.

Conclusions:

  • The study comprehensively defines the recognition mechanism between APC and Amer1.
  • A consensus recognition sequence employed by multiple APC-ARM binding partners was revealed.
  • Disruption of these interfaces abrogates APC-Amer1 association and impairs APC membrane recruitment in cells.
Keywords:
APCARM domainAmer1WTXconsensus recognition modecrystal structure

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