Li, Y., Wei, Z., Yan, Y., Wan, Q., Du, Q., & Zhang, M. (2014).  Proceedings of the National Academy of Sciences, 111(49), 17444-17449.

The Crumbs (Crb) complex, formed by Crb, PALS1, and PATJ, is evolutionarily conserved in metazoans and acts as a master cellgrowth and -polarity regulator at the apical membranes in polarized epithelia. Crb intracellular functions, including its direct binding to PALS1, are mediated by Crb’s highly conserved 37-residue cytoplasmic tail. However, the mechanistic basis governing the highly specific Crb– PALS1 complex formation is unclear, as reported interaction between the Crb tail (Crb-CT) and PALS1 PSD-95/DLG/ZO-1 (PDZ) domain is weak and promiscuous. Here we have discovered that the PDZ–Src homolgy 3 (SH3)–Guanylate kinase (GK) tandem of PALS1 binds to Crb-CT with a dissociation constant of 70 nM, which is 100-fold stronger than the PALS1 PDZ–Crb-CT interaction. The crystal structure of the PALS1 PDZ–SH3–GK–Crb-CT complex reveals that PDZ–SH3–GK forms a structural supramodule with all three domains contributing to the tight binding to Crb. Mutations disrupting the tertiary interactions of the PDZ–SH3–GK supramodule weaken the PALS1–Crb interaction and compromise PALS1-mediated polarity establishment in Madin– Darby canine kidney (MDCK) cysts. We further show that specific target binding of other members of membrane-associated guanylate kinases (MAGUKs) (e.g., CASK binding to neurexin) also requires the presence of their PDZ–SH3–GK tandems.

Full text link

PDF avaliable