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Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α.

Chen KE, Tillu VA, Chandra M, Collins BM
Structure 26 1612-1625.e4 (2018)
Related entries: 6bty, 6btz, 6bu0

Cited: 18 times
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Abstract

Phosphorylation of phosphoinositides by the class II phosphatidylinositol 3-kinase (PI3K) PI3K-C2α is essential for many processes, including neuroexocytosis and formation of clathrin-coated vesicles. A defining feature of the class II PI3Ks is a C-terminal module composed of phox-homology (PX) and C2 membrane interacting domains; however, the mechanisms that control their specific cellular localization remain poorly understood. Here we report the crystal structure of the C2 domain of PI3K-C2α in complex with the phosphoinositide head-group mimic inositol hexaphosphate, revealing two distinct pockets for membrane binding. The C2 domain preferentially binds to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate, and low-resolution structures of the combined PX-C2 module by small-angle X-ray scattering reveal a compact conformation in which cooperative lipid binding by each domain binding can occur. Finally, we demonstrate an unexpected role for calcium in perturbing the membrane interactions of the PX-C2 module, which we speculate may be important for regulating the activity of PI3K-C2α.

Reviews - 6bub mentioned but not cited (1)

  1. Advances in chemical proteomic evaluation of lipid kinases-DAG kinases as a case study. Ware TB, Hsu KL. Curr Opin Chem Biol 65 101-108 (2021)

Articles - 6bub mentioned but not cited (1)

  1. Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers. Kervin TA, Overduin M. Cells 10 1205 (2021)


Reviews citing this publication (8)

  1. Class II PI3Ks at the Intersection between Signal Transduction and Membrane Trafficking. Margaria JP, Ratto E, Gozzelino L, Li H, Hirsch E. Biomolecules 9 E104 (2019)
  2. PI3K inhibitors in thrombosis and cardiovascular disease. Durrant TN, Hers I. Clin Transl Med 9 8 (2020)
  3. The Ins and Outs of RAS Effector Complexes. Kiel C, Matallanas D, Kolch W. Biomolecules 11 236 (2021)
  4. Computational Structural Biology: Successes, Future Directions, and Challenges. Nussinov R, Tsai CJ, Shehu A, Jang H. Molecules 24 E637 (2019)
  5. Beyond PI3Ks: targeting phosphoinositide kinases in disease. Burke JE, Triscott J, Emerling BM, Hammond GRV. Nat Rev Drug Discov 22 357-386 (2023)
  6. Class II phosphatidylinositol 3-kinase isoforms in vesicular trafficking. Yoshioka K. Biochem Soc Trans 49 893-901 (2021)
  7. Critical role of lipid membranes in polarization and migration of cells: a biophysical view. Sackmann E, Tanaka M. Biophys Rev 13 123-138 (2021)
  8. Phosphoinositides and intracellular calcium signaling: novel insights into phosphoinositides and calcium coupling as negative regulators of cellular signaling. Oh BC. Exp Mol Med 55 1702-1712 (2023)

Articles citing this publication (8)

  1. Classification of the human phox homology (PX) domains based on their phosphoinositide binding specificities. Chandra M, Chin YK, Mas C, Feathers JR, Paul B, Datta S, Chen KE, Jia X, Yang Z, Norwood SJ, Mohanty B, Bugarcic A, Teasdale RD, Henne WM, Mobli M, Collins BM. Nat Commun 10 1528 (2019)
  2. Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context. Ibáňez Gaspar V, Catozzi S, Ternet C, Luthert PJ, Kiel C. Small GTPases 12 209-225 (2021)
  3. TGFβ receptor endocytosis and Smad signaling require synaptojanin1, PI3K-C2α-, and INPP4B-mediated phosphoinositide conversions. Aki S, Yoshioka K, Takuwa N, Takuwa Y. Mol Biol Cell 31 360-372 (2020)
  4. Binding of Ca2+-independent C2 domains to lipid membranes: A multi-scale molecular dynamics study. Larsen AH, Sansom MSP. Structure 29 1200-1213.e2 (2021)
  5. Structural basis of phosphatidylinositol 3-kinase C2α function. Lo WT, Zhang Y, Vadas O, Roske Y, Gulluni F, De Santis MC, Zagar AV, Stephanowitz H, Hirsch E, Liu F, Daumke O, Kudryashev M, Haucke V. Nat Struct Mol Biol 29 218-228 (2022)
  6. De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex. Chen KE, Guo Q, Hill TA, Cui Y, Kendall AK, Yang Z, Hall RJ, Healy MD, Sacharz J, Norwood SJ, Fonseka S, Xie B, Reid RC, Leneva N, Parton RG, Ghai R, Stroud DA, Fairlie DP, Suga H, Jackson LP, Teasdale RD, Passioura T, Collins BM. Sci Adv 7 eabg4007 (2021)
  7. An Overview of Class II Phosphoinositide 3-Kinases. Heng EYZ, Maffucci T. Curr Top Microbiol Immunol 436 51-68 (2022)
  8. Structural Insights into the Mechanism of HIV-1 Tat Secretion from the Plasma Membrane. Ghanam RH, Eastep GN, Saad JS. J Mol Biol 435 167880 (2023)


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