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Review
. 2004 Jun 1;101(22):8262-9.
doi: 10.1073/pnas.0401874101. Epub 2004 May 14.

Protein-lipid interactions and phosphoinositide metabolism in membrane traffic: insights from vesicle recycling in nerve terminals

Markus R Wenk  1 , Pietro De Camilli
Affiliations
Review

Protein-lipid interactions and phosphoinositide metabolism in membrane traffic: insights from vesicle recycling in nerve terminals

Markus R Wenk et al. Proc Natl Acad Sci U S A. .

Abstract

Great progress has been made in the elucidation of the function of proteins in membrane traffic. Less is known about the regulatory role of lipids in membrane dynamics. Studies of nerve terminals, compartments highly specialized for the recycling of synaptic vesicles, have converged with studies from other systems to reveal mechanisms in protein-lipid interactions that affect membrane shape as well as the fusion and fission of vesicles. Phosphoinositides have emerged as major regulators of the binding of cytosolic proteins to the bilayer. Phosphorylation on different positions of the inositol ring generates different isomers that are heterogeneously distributed on cell membranes and that together with membrane proteins generate a "dual keys" code for the recruitment of cytosolic proteins. This code helps controlling vectoriality of membrane transport. Powerful methods for the detection of lipids are rapidly advancing this field, thus complementing the broad range of information about biological systems that can be obtained from genomic and proteomic approaches.

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Figures

Fig. 1.
Fig. 1.
Vesicle traffic in nerve terminals and putative relationship to phosphoinositide metabolism. Membranes are color-coded based on their putative content in specific phosphoinositide species. The synaptic vesicle traffic is shown at left. PI(4)P is thought to be present on synaptic vesicles (SVs), whereas PI(4,5)P2 (dark green) is selectively concentrated in the plasma membrane (PM). During intense activity, deep plasma membrane invaginations and endosome-like (EL) structures generated form their fission retrieve excess membrane before clathrin-mediated budding (24). At right, the classical clathrin-mediated recycling pathway, which in nerve terminals may participate in receptors, transporters and channels endocytosis, is illustrated. Based on work in other systems, presence of PI(3)P (light blue) and PI(3,5)P2 (dark blue) on early (EE) and late (LE) endosomes, respectively, is proposed. PI(3,4,5)P3, which is generated by PI3-kinases associated with growth factor receptor signaling, is shown in red. The relationship of classical early endosomes to endosome-like structures that participate in synaptic vesicle recycling (a compartment that undergoes transient expansion during intense stimulation) remains to be elucidated.
Fig. 2.
Fig. 2.
Morphological changes of lipid vesicles caused by incubation with cytosolic proteins. (A and B) Unilamellar liposomes before and after incubation with rat brain cytosol and nucleotides. Clathrin-coated profiles (arrowheads) that closely resemble those observed in situ are visible in B. (C) Incubation of liposomes with purified amphiphysin, a clathrin and dynamin interacting protein, leads to massive tubulation. Liposomes were analyzed by electron microscopy after plastic embedding and thin sectioning (A and B)or negative staining (C). (Scale bar = 100 nm in A, 200 nm in B, and 250 nm in C.) [B reproduced with permission from ref. (Copyright 1998, Elsevier, Amsterdam).] [C reproduced with permission from ref. (Copyright 2003, Elsevier, Amsterdam).]
Fig. 3.
Fig. 3.
Profiling of PIs in a brain lipid extract by electrospray ionization mass spectrometry. (Upper) Negative ion single stage mass spectrum of a total rat brain lipid extract. A large number of ions are detected in the mass range of m/z 700-900, where the majority of phospholipids species cluster. Phosphorylation of the major PI species, 38:4 PI, shifts the corresponding PIP (38:4 PI, m/z 965) by 80 units, the mass of a phosphate moiety. Less abundant PIP species are detected by precursor ion scanning (Lower). A precursor ion scan for m/z 321 (the inositol headgroup of PIP) yields clusters of PIP species with 34, 36, 38, and 40 fatty acid carbons (Lower), whose structures are shown in color (blue, C16:0, palmitic acid; green, C18:0, stearic acid; magenta, C18:1, oleic acid; yellow, C20:4, arachidonic acid; red, C22:6, docosahexaenoic acid) (49).
Fig. 4.
Fig. 4.
PIs as part of a coincidence detection mechanism for the recruitment of cytosolic proteins. PI(4)P and PI(4,5)P2 function as coreceptors together with intrinsic membrane proteins in the recruitment of AP-1 and AP-2 clathrin adaptors at the Golgi complex and on the plasma membrane, respectively. (Lower) Schematic representation of two clathrin adaptors, epsin and Hrs, that contain a phosphoinositide-binding domain and ubiquitin-interacting domains (UIM) (143). These proteins are thought to participate in the sorting of monoubiquitinated membrane proteins. Hrs, which is localized on endosomes, binds PI(3)P via a Fyve domain, whereas epsin, localized primarily at the plasma membrane, binds PI(4,5)P2 via an ENTH domain. Additional interactions with components of the membrane may be mediated by the ENTH and VHS domains, respectively. Binding sites for clathrin coat components are located in unfolded low-complexity COOH-terminal half of epsin and Hrs (black line).
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References

    1. Jahn, R., Lang, T. & Sudhof, T. C. (2003) Cell 112, 519-533. - PubMed
    1. Rothman, J. E. (2002) Nat. Med. 8, 1059-1062. - PubMed
    1. Israelachvili, J. N. & Mitchell, D. J. (1975) Biochim. Biophys. Acta 389, 13-19. - PubMed
    1. Chernomordik, L., Kozlov, M. M. & Zimmerberg, J. (1995) J. Membr. Biol. 146, 1-14. - PubMed
    1. Burger, K. N. (2000) Traffic 1, 605-613. - PubMed

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