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Article (Published Version) Article Cooperative binding of the tandem WW domains of PLEKHA7 to PDZD11 promotes conformation-dependent interaction with tetraspanin 33 ROUAUD, Florian, et al. Abstract Pleckstrin homology domain-containing A7 (PLEKHA7) is a cytoplasmic protein at adherens junctions that has been implicated in hypertension, glaucoma, and responses to Staphylococcus aureus α-toxin. Complex formation between PLEKHA7, PDZ domain-containing 11 (PDZD11), tetraspanin 33, and the α-toxin receptor ADAM metallopeptidase domain 10 (ADAM10) promotes junctional clustering of ADAM10 and α-toxin-mediated pore formation. However, how the N-terminal region of PDZD11 interacts with the N-terminal tandem WW domains of PLEKHA7 and how this interaction promotes tetraspanin 33 binding to the WW1 domain is unclear. Here, we used site-directed mutagenesis, glutathione S-transferase pulldown experiments, immunofluorescence, molecular modeling, and docking experiments to characterize the mechanisms driving these interactions. We found that Asp-30 of WW1 and His-75 of WW2 interact through a hydrogen bond and, together with Thr-35 of WW1, form a binding pocket that accommodates a polyproline stretch within the N-terminal PDZD11 region. By strengthening the interactions of the ternary complex, the WW2 domain stabilized the WW1 [...] Reference ROUAUD, Florian, et al. Cooperative binding of the tandem WW domains of PLEKHA7 to PDZD11 promotes conformation-dependent interaction with tetraspanin 33. Journal of Biological Chemistry, 2020, vol. 295, no. 28, p. 9299-9312 DOI : 10.1074/jbc.RA120.012987 PMID : 32371390 Available at: http://archive-ouverte.unige.ch/unige:144944 Disclaimer: layout of this document may differ from the published version. 1 / 1 ARTICLE Author’s Choice Cooperative binding of the tandem WW domains of PLEKHA7 to PDZD11 promotes conformation-dependent interaction with tetraspanin 33 Received for publication, February 11, 2020, and in revised form, April 30, 2020 Published, Papers in Press, May 5, 2020, DOI 10.1074/jbc.RA120.012987 Florian Rouaud1,2, Francesca Tessaro3 , Laura Aimaretti3, Leonardo Scapozza3, and Sandra Citi1,2,* From the 1Department of Cell Biology, Faculty of Sciences and the 2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland, and the 3Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, and Institute of Pharmaceutical Sciences of Western Switzerland University of Geneva, Geneva, Switzerland Edited by Phyllis I. Hanson Pleckstrin homology domain–containing A7 (PLEKHA7) is At the tissue and organism level, PLEKHA7 has been impli- a cytoplasmic protein at adherens junctions that has been cated in morphogenesis and disease. Genome-wide associa- implicated in hypertension, glaucoma, and responses to tion studies show that single nucleotide polymorphism in the Downloaded from Staphylococcus aureus a-toxin. Complex formation between PLEKHA7 gene are associated with human hypertension and PLEKHA7, PDZ domain–containing 11 (PDZD11), tetraspanin high systolic pressure (5), and with primary angle closure glau- 33, and the a-toxin receptor ADAM metallopeptidase domain coma (6). In agreement, rats KO for PLEKHA7 show an atte- 10 (ADAM10) promotes junctional clustering of ADAM10 and nuated increase in blood pressure and kidney damage induced a-toxin–mediated pore formation. However, how the N-termi- by a high salt diet, and increased intracellular calcium and ni- http://www.jbc.org/ nal region of PDZD11 interacts with the N-terminal tandem trous oxide signaling in endothelial cells (7). In a zebrafish WW domains of PLEKHA7 and how this interaction promotes model, the PLEKHA7 homolog Hadp1 is required for cardiac tetraspanin 33 binding to the WW1 domain is unclear. Here, morphogenesis and contractility (8). PLEKHA7 has also been S we used site-directed mutagenesis, glutathione -transferase involved in the control of microRNA processing (9, 10) and pulldown experiments, immunofluorescence, molecular mod- Rho GTPase activity (11). In cultured cells and mice, PLEKHA7 at Université de Genève on October 14, 2020 eling, and docking experiments to characterize the mechanisms is required to make cells more susceptible to the cytotoxic driving these interactions. We found that Asp-30 of WW1 and effects of Staphylococcus aureus a-toxin, through a mechanism His-75 of WW2 interact through a hydrogen bond and, to- gether with Thr-35 of WW1, form a binding pocket that that involves junctional clustering of ADAM10, mediated by tet- accommodates a polyproline stretch within the N-terminal raspanin 33 (Tspan33) (12, 13). PDZD11 region. By strengthening the interactions of the ter- Considering the important roles of PLEKHA7 in physiology nary complex, the WW2 domain stabilized the WW1 domain and disease, it is crucial to understand the molecular, cellular, and cooperatively promoted the interaction with PDZD11. and structural basis for its functions. PLEKHA7 comprises N- Modeling results indicated that, in turn, PDZD11 binding terminal tandem WW, pleckstrin homology, and coiled-coil induces a conformational rearrangement, which strengthens domains, and interacts with different junctional proteins (1, 3, the ternary complex, and contributes to enlarging a “hydropho- 14) and membrane phospholipids (8). We identified PDZD11 bic hot spot” region on the WW1 domain. The last two lipo- as the highest affinity interactor of PLEKHA7 using 2-hybrid philic residues of tetraspanin 33, Trp-283 and Tyr-282, were screens and proteomic approaches, and showed that the inter- required for its interaction with PLEKHA7. Docking of the tetra- action of the N-terminal region of PDZD11 with the WW1 do- spanin 33 C terminus revealed that it fits into the hydrophobic main of PLEKHA7 is essential to cluster the Ig-like adhesion hot spot region of the accessible surface of WW1. We conclude molecules nectins at adherens junctions, and promote efficient that communication between thetwotandemWWdomainsof junction assembly (15). The same interaction is also required to – PLEKHA7 and the PLEKHA7 PDZD11 interaction modulate the dock the Staphylococcus aureus a-toxin receptor ADAM10 at ligand-binding properties of PLEKHA7. junctions, through binding of the WW1 domain of PLEKHA7 to the ADAM10 chaperone Tspan33 (13). Thus, the interaction with Cell-cell junctions are implicated in developmental, physio- PDZD11 is critical in mediating the activity of PLEKHA7 as a scaf- logical, and pathological processes. PLEKHA7, a protein local- fold for transmembrane proteins, such as nectins and Tspan33. ized at cadherin-based adherens junctions, was originally dis- However, nothing is known about the structural basis for the inter- covered as an interactor of p120-catenin (1) and paracingulin action of PLEKHA7 with PDZD11, and the mechanisms through (2, 3), and its interaction with microtubules, through the which PDZD11 promotes PLEKHA7 binding to Tspan33. minus-end binding protein nezha/CAMSAP3, stabilizes cad- WW domains are domains of 35-40 amino acids, character- herin-based junctions and the barrier function of epithelia (1, 4). ized by two highly conserved Trp residues, separated by 20 to 23 amino acids. WW domains fold into a very stable structure This article contains supporting information. with three antiparallel b-sheets, and can accommodate a high Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license. degree of sequence variability (16, 17). They typically bind ei- * For correspondence: Sandra Citi, [email protected]. ther to proline-rich sequences or phosphorylated Ser or Thr J. Biol. Chem. (2020) 295(28) 9299–9312 9299 © 2020 Rouaud et al. Published by The American Society for Biochemistry and Molecular Biology, Inc. Cooperative PLEKHA7-PDZD11-Tspan33 interaction residues, and are found in many human proteins, which play interacted with PDZD11 as efficiently as WT, and none with important roles in nuclear signaling, protein stabilization, the CFP-HA (Fig. 1D). In addition, Ponceau S staining of GST assembly of multiprotein networks, and diseases (18–20). fusion proteins showed no degradation, because all fusion pro- Because of the critical importance of the PDZD11 interaction teins migrated as one major polypeptide (Fig. 1D, Ponceau, red in PLEKHA7 function, we sought to gain further insights into arrows). These results suggest that the presence of the WW2 the structural aspects of the interaction between the WW domain stabilizes the WW1 domain. Next, to obtain separate domains of PLEKHA7 and PDZD11, using site-directed muta- evidence that these results reflect physiologically relevant genesis, GST (glutathione-S-transferase) pulldown assays, and mechanisms and interactions, we examined the effect of WW1 immunofluorescence. Our data allows to generate a model for mutations on the interaction between full-length PLEKHA7 the structure of the complex using molecular modeling and and PDZD11 in cells. PLEKHA7 recruits PDZD11 to junctions docking studies, which provides a rational mechanism through (15), and we used as a readout the rescue of the junctional local- which intramolecular WW1–WW2 interactions promote ization of PDZD11, which is abolished in PLEKHA7-KO cells, binding to PDZD11, and this in turn promotes interaction with by different WW domain mutants of PLEKHA7. In PLEKHA7- Tspan33. KO cells transfected with GFP alone, no PDZD11 labeling was detected at junctions (negative control, Fig. 1E, 1GFP, arrow- Results heads). In contrast, endogenous PDZD11 was rescued to junc- Specific mutations
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