MAGUKs end a tale of promiscuity.

Abstract

Membrane-associated guanylate kinases (MAGUKs) constitute a family of scaffold molecules involved in diverse cellular processes, such as cell–cell communication, cell polarity, and signal transduction (1). MAGUKs are multidomain proteins with a core structure consisting of PSD-95/DLG/ZO-1 (PDZ), Src homolgy 3 (SH3), and enzymatically inactive guanylate kinase (GK) domains. Although full-length MAGUKs generally display a high degree of binding specificity, binding studies with isolated PDZ domains often show the ability to interact with numerous partners (2). In PNAS, Li et al. (3) provide a conclusive structural answer to this discrepancy. The authors have solved the crystal structure of a PALS1/Crb complex that demonstrates why the PDZ–SH3–GK supramodule of PALS1, but not the isolated PDZ domain, binds with an extraordinarily high affinity to the C terminus of Crb (3). Domains in the supramodule are arranged in a way that a peptide comprising the last 17 residues of Crb binds simultaneously to the PDZ, the SH3 and, most surprisingly, to the GK domain using two distinct sites. The C-terminal fixation in the PDZ binding groove follows an expected main chain connectivity of PDZ/peptide complexes. Interestingly, residues of the SH3 domain collaborate in peptide binding by building a kind of a clasp. Using site-directed mutagenesis, Li et al. (3) prove that the clasp accounts for the high affinity and specificity of Crb binding to PALS1. This discovery has immediate consequences for other MAGUKs, for example at synapses in the brain, because the authors propose that sequence variations within the clasp-loop are responsible for defining their specificity. As proof-of-principle, Li et al. show that the C terminus of neurexin does not bind to the isolated PDZ but to the PDZ–SH3–GK supramodule of calcium/calmodulin-dependent serine protein … [↵][1]1To whom correspondence may be addressed. Email: creissn{at}uni-muenster.de or markus.missler{at}uni-muenster.de. [1]: #xref-corresp-1-1