Recombinant Protein Biosensors of Cell Membrane Lipids

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Abstract

Specific patterns of lipid distribution in cell membranes determine their structural and signaling roles, and ensure the integrity and functionality of the plasma membrane and cell organelles. Recent advances in the development of recombinant lipid biosensors and imaging techniques allow direct observation of the distribution, movement, and dynamics of lipids within cells, significantly expanding the understanding of lipid functions and their involvement in cellular and subcellular processes. In this review, we summarize the data related to the development and application of recombinant protein sensors for various lipids in cell membranes.

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About the authors

E. M. Koltsova

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology; Center of Theoretical Problems of Physico-chemical Pharmacology of the Russian Academy of Sciences

Author for correspondence.
Email: ekaterina_koltsova@bk.ru
Russian Federation, Moscow, 117997; Moscow, 109029

N. A. Kolchin

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology; Center of Theoretical Problems of Physico-chemical Pharmacology of the Russian Academy of Sciences

Email: ekaterina_koltsova@bk.ru
Russian Federation, Moscow, 117997; Moscow, 109029

E. I. Nikolaeva

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology; Center of Theoretical Problems of Physico-chemical Pharmacology of the Russian Academy of Sciences

Email: ekaterina_koltsova@bk.ru
Russian Federation, Moscow, 117997; Moscow, 109029

K. R. Butov

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology; Pirogov Russian National Research Medical University

Email: ekaterina_koltsova@bk.ru
Russian Federation, Moscow, 117997; Moscow, 117513

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2. Fig. 1. Major classes of lipids in mammalian cells. The designations R1 and R2 indicate the position of fatty acid chains. The site of attachment of polar head groups of basic glycerophospholipids to phosphatidic acid is indicated by red lines.

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3. Fig. 2. Structure of the phosphatidylcholine-binding C2 domain of phospholipase A2 (PLA2C2, Protein Data Bank (PDB) code 1RLW). Ca2+ ions required for binding of the domain to the membrane are indicated in blue. Red color indicates hydrophobic side chains of amino acid residues embedded in the hydrocarbon backbone of the membrane when the domain binds to the membrane [23, 24].

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4. Fig. 3. Structure of phosphatidylserine-binding domains and proteins. Binding of the “annexin core” of annexin A5 (PDB code 1A8A) to the membrane through ten coordinated Ca2+ ions (marked in blue) forming “bridges” between the protein and the membrane is shown [93, 94]. The binding of the C2 domain of lactadherin (LactC2, PDB code 3BN6), PH domain of ejectin-2 (PH evt-2, PDB code 3VIA), and Tim4 (PDB code 3BIB) is accomplished by introducing hydrophobic side chains of amino acid residues into the hydrocarbon backbone of the membrane (indicated in red) [26, 95, 96].

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5. Fig. 4. Structure of the main types of phosphatidylinositol-binding domains and proteins. Examples for each type include the PI-specific bacterial phospholipase C (BcPI-PLC H82A, PDB code 6S2A) [32, 119], the dimerized FYVE domain of early endosomal antigen-1 (FYVE-EEA1x2, PDB code 1JOC), structurally essential Zn2+ ions are indicated in orange [120], PX domain of NADPH-oxidase p40phox (PX-p40phox, PDB code 1H6H) [121], PH domain of phospholipase C gamma 1 (PLCδ1-PH, PDB code 1MAI) [122], P4C- and P4M-domains of bacterial proteins SidC (P4C-SidC, PDB code 4TRH) [117] and SidM (P4M-SidM, PDB code 4MXP) [118]. Binding is accomplished by introducing hydrophobic side chains of amino acid residues into the hydrocarbon backbone of the membrane (indicated in red).

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