At least 10 different types of globular protein domain are known that bind membrane phospholipids. Acidic phospholipids (especially phosphatidylserine and phosphoinositides) are the primary binding targets.
Phospholipid-binding domains vary widely in their degree of ligand specificity. Some are highly target specific, whereas others will bind to any acidic phospholipid.
Target-specific domains include conserved region-1 (C1) domains (which specifically recognize diacylglycerol), specific phosphoinositide-binding domains (certain pleckstrin homology (PH) domains, Phox homology (PX) domains, FYVE (Fab1, YOTB, Vac1, EEA1) domains and PROPPINs (β-propellers that bind phosphoinositides)), and certain phosphatidylserine-binding domains (especially extracellular domains). Membrane binding by these domains is typically dictated simply by the presence or absence of the (rare) target lipid in membranes.
The target lipids for highly specific membrane-binding proteins are often lipid second messengers (for example, diacylglycerol and phosphoinositide 3-kinase (PI3K) products).
Membrane association of domains without precise target specificity is typically regulated by soluble second messengers (Ca2+ for annexins and C2 domains) or by the local curvature of membranes.
Several phospholipid-binding domains (ENTH domains, BAR-family members and tandem C2 domains) appear to induce or sense membrane curvature.
Cooperation between binding sites is a frequently occurring theme in membrane-targeting events. The different sites may occur in the same domain (as in some PH and PX domains) or in different domains in a multidomain protein.
Domain–domain cooperation allows 'coincidence detection' in membrane association, whereby a given protein is only targeted to membranes that contain a particular combination of lipids (or lipids and proteins).
Many different globular domains bind to the surfaces of cellular membranes, or to specific phospholipid components in these membranes, and this binding is often tightly regulated. Examples include pleckstrin homology and C2 domains, which are among the largest domain families in the human proteome. Crystal structures, binding studies and analyses of subcellular localization have provided much insight into how members of this diverse group of domains bind to membranes, what features they recognize and how binding is controlled. A full appreciation of these processes is crucial for understanding how protein localization and membrane topography and trafficking are regulated in cells.
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I thank K. Ferguson and members of the Lemmon laboratory for comments on this review. Work in this area in my laboratory is funded by the National Institute of General Medical Sciences (NIGMS).
RCSB Protein Data Bank
- Inner leaflet
A lipid layer that faces the inside of the cell.
Specific recognition of a particular stereoisomer in a binding reaction.
Possession of both hydrophobic and hydrophilic regions.
- Second messengers
Molecules that act in a cell to promote responses to extracellular stimuli.
- Phorbol esters
Polycyclic esters that are isolated from croton oil. The most common are phorbol-12-myristate-13-acetate and 12-O-tetradecanoyl-phorbol-13-acetate. These are both potent carcinogens or tumour promoters because they mimic diacylglycerol and thereby irreversibly activate protein kinase C.
- Zinc finger
A small structural motif that is found in many proteins, including phospholipid-binding proteins, DNA-binding proteins and ubiquitin ligases. Zinc fingers are characterized by particular sequences of cysteines and histidines that coordinate bound Zn2+ ions. The bound Zn2+ ions are structurally crucial, and their ability to nucleate the protein structure obviates the need for a hydrophobic core.
- Guanine nucleotide-exchange factor
A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.
A disorder that is caused by an inability to make mature B cells and, as a result, antibodies. X-linked agammaglobulinaemia can arise from mutations in the PH domain of Bruton's tyrosine kinase (BTK) that block the ability of BTK to respond to phosphoinositide 3-kinase signalling. Activation of BTK is crucial for B-cell maturation.
- GTPase-activating proteins
(GAPs). Proteins that stimulate the intrinsic ability of a GTPase to hydrolyse GTP to GDP. GAPs negatively regulate GTPases by converting them from active states (GTP bound) to inactive states (GDP bound).
- Split PH domain
A pleckstrin homology (PH) domain with an interrupted sequence. Regions of polypeptide that are well separated in the primary sequence of a protein can interact with one another to form a globular PH domain fold. The interruptions are usually in the flexible loops of the PH domain and can harbour other domains.
(Endosomal sorting complex required for transport). The multiprotein ESCRT machinery (ESCRT-I, -II and -III) promotes inward vesiculation at the limiting membrane of the sorting endosome and selects cargo proteins for delivery to the intralumenal vesicles of multivesicular bodies.
Vesicles that are formed by invagination of the plasma membrane.
- Multivesicular bodies
Endosomal intermediates in which small membrane vesicles are enclosed in a limiting membrane. The internal vesicles are thought to form by invagination and budding from the limiting membrane.
Membrane-bound vesicles that contain microorganisms or particulate material from the extracellular environment.
The overall measure of binding between a multivalent ligand and its receptors, which reflects the combined strength of multiple binding sites. Avidity was originally defined for antibodies, for which it refers to the overall strength of binding between multivalent antigens and antibodies.
- Coiled-coil domain
A protein structural domain that often mediates subunit oligomerization. Coiled coils contain between two and five α-helices that twist around each other to form a supercoil.
- Sorting nexin
Also known as SNX proteins. These proteins are characterized by the presence of Phox-homology (PX) domains and play roles in endosomal cargo sorting as well as other functions.
A complex of five proteins (Vps35, Vps26, Vps29, Vps17 and Vps5 in yeast) that is important for recycling transmembrane proteins from endosomes to the trans-Golgi network.
- Zwitterionic phospholipids
A phospholipid with a headgroup that is electrically neutral (no net charge), but that has formal positive and negative charges on different groups. For example, phosphatidylcholine has a positively charged choline headgroup and a negatively charged phosphate. Phosphatidylethanolamine and sphingomyelin are also zwitterionic phospholipids.
The proteolysis of fibrin by plasmin in blood clots.
A pro-enzyme form of thrombin (also known as factor II), a serine protease that is involved in the blood coagulation cascade by converting fibrinogen into insoluble fibrin.
- Factors V, VII, VIII, IX and X
Coagulation factors. Factors VII, IX and X are serine protease pro-enzymes that are involved in the blood coagulation cascade. Once activated, factors V and VIII are cofactors for factor Xa and IXa, respectively.
An integral membrane protein with two PKC-class C2 domains that acts as a Ca2+ sensor in Ca2+-triggered synaptic vesicle fusion with the plasma membrane.
A large self-assembling GTPase that plays a crucial role in the scission of endocytic vesicles from the plasma membrane.
- Coated pit
An invagination in the plasma membrane, coated with clathrin on its cytoplasmic face, that becomes internalized and forms a clathrin-coated endocytic vesicle.
Thin, transient actin protrusions that extend out from the cell surface and that are formed by the elongation of bundled actin filaments that exist in its core.
- SH2 domain
(Src homology 2). A small protein domain (110 amino acids) that is found in many signalling proteins and that recognizes phosphorylated tyrosine residues in a particular sequence context. SH2 domains are responsible for recruiting downstream signalling molecules to activated receptor tyrosine kinases at the cell surface.
- SH3 domain
(Src homology 3). A small protein domain (50–60 amino acids) that recognizes proline-rich sequences that are important for the assembly of various different signalling complexes.
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Lemmon, M. Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol 9, 99–111 (2008). https://doi.org/10.1038/nrm2328
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