Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 297, Issue 5, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2021.101289
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Funding
- National Institutes of Health [AR44016, AR057992, GM0113922]
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The concave surface of Scribble's LRR domain can interact with proteins in three mutually exclusive ways: self-inhibition, formation of multiprotein complexes, and direct interaction with the protein phosphatase PP1. This organization may create a dynamic signaling network that allows for rapid dephosphorylation kinetics.
Scribble, a member of the LAP protein family, contributes to the apicobasal polarity (ABP) of epithelial cells. The LAPunique region of these proteins, which is essential and sufficient for ABP, includes a conserved Leucine-Rich Repeat (LRR) domain. The major binding partners of this region that could regulate ABP remain unknown. Here, using proteomics, native gel electrophoresis, and site-directed mutagenesis, we show that the concave surface of LRR domain in Scribble participates in three types of mutually exclusive interactions-(i) homodimerization, serving as an auto-inhibitory mechanism; (ii) interactions with a diverse set of polarity proteins, such as Llgl1, Llgl2, EPB41L2, and EPB41L5, which produce distinct multiprotein complexes; and (iii) a direct interaction with the protein phosphatase, PP1. Analogy with the complex between PP1 and LRR domain of SDS22, a well-studied PP1 regulator, suggests that the Scibble-PP1 complex stores a latent form of PP1 in the basolateral cell cortex. Such organization may generate a dynamic signaling network wherein PP1 could be dispatched from the complex with Scribble to particular protein ligands, achieving fast dephosphorylation kinetics.
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