Structural basis for the association of PLEKHA7 with membrane-embedded phosphatidylinositol lipids. Structure 2021 Sep 02;29(9):1029-1039.e3
Date
04/21/2021Pubmed ID
33878292Pubmed Central ID
PMC8419008DOI
10.1016/j.str.2021.03.018Scopus ID
2-s2.0-85107072903 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
PLEKHA7 (pleckstrin homology domain containing family A member 7) plays key roles in intracellular signaling, cytoskeletal organization, and cell adhesion, and is associated with multiple human cancers. The interactions of its pleckstrin homology (PH) domain with membrane phosphatidyl-inositol-phosphate (PIP) lipids are critical for proper cellular localization and function, but little is known about how PLEKHA7 and other PH domains interact with membrane-embedded PIPs. Here we describe the structural basis for recognition of membrane-bound PIPs by PLEHA7. Using X-ray crystallography, nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the interaction of PLEKHA7 with PIPs is multivalent, distinct from a discrete one-to-one interaction, and induces PIP clustering. Our findings reveal a central role of the membrane assembly in mediating protein-PIP association and provide a roadmap for understanding how the PH domain contributes to the signaling, adhesion, and nanoclustering functions of PLEKHA7.
Author List
Aleshin AE, Yao Y, Iftikhar A, Bobkov AA, Yu J, Cadwell G, Klein MG, Dong C, Bankston LA, Liddington RC, Im W, Powis G, Marassi FMAuthor
Francesca M. Marassi PhD Chair, Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Binding SitesCarrier Proteins
Cell Membrane
Humans
Lipid Bilayers
Phosphatidylinositols
Protein Binding
