Structural basis for tandem L27 domain-mediated polymerization

Abstract

The establishment of epithelial cell polarity requires the assembly of multiprotein complexes and is crucial during epithelial morphogenesis. Three scaffolding proteins, Dlg1, MPP7, and Mals3, can be assembled to form a complex that functions in the establishment and maintenance of apicobasal polarity in epithelial tissues through their L27 domains. Here we report the crystal structure of a 4-L27-domain complex derived from the human tripartite complex Dlg1-MPP7-Mals3 in combination with paramagnetic relaxation enhancement measurements. The heterotrimer consists of 2 pairs of heterodimeric L27 domains. These 2 dimers are asymmetric due to the large difference between the N- and C-terminal tandem L27 domain of MPP7. Structural analysis combined with biochemical experiments further reveals that the loop αA-αB and helix αB of the C-terminal L27 domain of MPP7 play a critical role in assembling the entire tripartite complex, suggesting a synergistic tandem L27-mediated assembling event.

Structure of an L27 Domain Heterotrimer from Cell Polarity Complex Patj/Pals1/Mals2 Reveals Mutually Independent L27 Domain Assembly Mode

“…3A), indicating that each L27 heterodimer is formed mutually independently. This result contrasts sharply with previous findings that two L27 heterodimers are asymmetric and cooperative in the L27 DLG1 /(L27N-L27C) MPP7 /L27 Mals3 heterotrimeric complex (21). To verify our findings, we performed a GST pulldown assay.…”

“…Recently, the structure of a tandem L27 domain-mediated tripartite L27 DLG1 /(L27N-L27C) MPP7 / L27 Mals3 complex showed the asymmetric, cooperative assembly of a heterotrimer consisting of two cognate pairs of heterodimeric L27 domains (21).…”

Event inference in multidomain families with phylogenetic reconciliation

“…Our analysis predicts that MPP2/6 are more likely to be similar to MPP3/7 , with respect to L27 mediated interactions. This is consistent with recent experimental results that show that MPP2, MPP3 , and MPP7 share a common L27 -mediated complex formation mechanism, while CASK uses a different mechanism [ 65 ].…”

Association of the Synapse-Associated Protein 97 (SAP97) Gene Polymorphism With Neurocognitive Function in Schizophrenic Patients

“…The SNP rs3915512 is located in an important region of the SAP97 gene where it is transcribed into a portion of the SAP97 mRNA that is further translated into a part of the L27 domain ( 10 ). As an assembly center for large proteins ( 23 ), the L27 domain can mediate the multimerization of scaffold proteins that are encoded by the SAP97 gene ( 24 ). Although it only interacts with multimeric scaffold proteins, NMDAR can trigger the recruitment of AMPARs into the synaptic membrane and thus plays a key role in synaptic plasticity ( 25 ), which is directly related to cognitive function ( 26 ).…”