9W5C

Complex structure of MAGI3 WW1 and IQSEC3 PPxY motif

Summary for 9W5C

• Entry DOI: 10.2210/pdb9w5c/pdb
• Descriptor: Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3, IQ motif and SEC7 domain-containing protein 3 (3 entities in total)
• Functional Keywords: magi3, iqsec3, ww-ppxy interaction, complex, extension sequence, protein binding
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 12
• Total formula weight: 43392.88

Authors

Wang, J.,Lin, L.,Zhu, J. (deposition date: 2025-08-01, release date: 2026-02-25, Last modification date: 2026-04-22)

Primary citation

Wang, J.,Li, Y.,Wu, Y.,Lin, L.,Zhu, J.
Extended motif recognition tunes WW domain affinity in MAGI-IQSEC complexes.
Febs J., 2026

PubMed Abstract: Many proteins containing WW domains interact with proline-rich PPxY motifs, raising questions regarding how they achieve specificity in cellular contexts. Here, we characterize the WW domain-mediated interactions between the MAGI and IQSEC protein families, which play critical roles in neurodevelopment and synaptic signaling. The high-resolution crystal structure of the MAGI3-IQSEC3 complex reveals that an extended sequence C terminus to the canonical PPxY motif in IQSEC3 engages a previously uncharacterized binding site on the WW1 domain of MAGI3. This extension interface enhances binding affinity by dozens-fold, and mutagenesis of key residues within this site abrogates complex formation, demonstrating its functional necessity. This bipartite recognition mode is evolutionarily conserved across MAGI and IQSEC family members. Our work elucidates the structural basis governing MAGI-IQSEC assembly and establishes a generalizable model whereby motif extensions enable high-affinity, specific target selection by WW domains, with broad implications for modular domain-mediated signaling networks.

PubMed: 41870210
DOI: 10.1111/febs.70509

Experimental method

X-RAY DIFFRACTION (2.1 Å)