High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine

Fairn, Gregory D.; Schieber, Nicole L.; Ariotti, Nicholas; Murphy, Samantha; Kuerschner, Lars; Webb, Richard I.; Grinstein, Sergio; Parton, Robert G.

doi:10.1083/jcb.201012028

Cited by 259 publications

(282 citation statements)

References 62 publications

(81 reference statements)

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“…An L(r)-r value above the 99% confidence interval demonstrates a nonrandom clustered distribution. Consistent with previous results, in wildtype (WT) cells we observed a nonrandom, clustered distribution of PS (Fairn et al, 2011;Cho et al, 2012; van der Hoeven Figure 2. Caveolin is essential for the regulation of K-Ras nanoclustering on the PM.…”

Section: Ras Nanoclusterssupporting

confidence: 80%

“…1 F). Ripley's K-function spatial point pattern analysis of PS was performed with control (shScrambled) and CAV1-kd BHK cells expressing mRFP-LactC2-a molecular probe that specifically associates with PS domains on the inner leaflet of the PM (Fairn et al, 2011;Kay et al, 2012). This analysis involves digitizing the spatial distributions of gold particles in a given region of interest (1 µm 2 of PM lawn) into a set of x and y coordinates.…”

Section: Ras Nanoclustersmentioning

confidence: 99%

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Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling

Ariotti¹,

Zhou²,

Hill³

et al. 2014

J Gen Physiol

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Section: Ras Nanoclusterssupporting

confidence: 80%

Section: Ras Nanoclustersmentioning

confidence: 99%

Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling

Ariotti¹,

Zhou²,

Hill³

et al. 2014

J Gen Physiol

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“…In conclusion, we have detected no indication that the MABP domain has significant specificity for any of the phosphoinositides of significance in the ESCRT pathway. If anything, the MABP domain shows a preference for PS, which is broadly distributed on the plasma membrane, trans-Golgi, and endosomal network (12). This preference is marginal, however, and, in conjunction with the open nature of the lipid-binding site, described below, lipid recognition by the MABP domain seems best characterized as charge-dependent but otherwise nonspecific.…”

Section: Resultsmentioning

confidence: 98%

“…Endosomes are enriched in PS (12). PI(3)P, a lipid that is intimately associated with the ESCRTs, has in common with PS that both lipids are incorporated into the intralumenal vesicles (ILVs) of MVBs (12,13). By taking the observation that PS is incorporated into ILVs in cells in combination with the in vitro preference of human ESCRT-I for PS, a functional connection between the ESCRTs and PS in ILV budding (34) seems plausible.…”

Section: Discussionmentioning

confidence: 99%

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Structural basis for membrane targeting by the MVB12-associated β-prism domain of the human ESCRT-I MVB12 subunit

Bouřa

Hurley

2012

Proc. Natl. Acad. Sci. U.S.A.

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MVB12-associated β-prism (MABP) domains are predicted to occur in a diverse set of membrane-associated bacterial and eukaryotic proteins, but their existence, structure, and biochemical properties have not been characterized experimentally. Here, we find that the MABP domains of the MVB12A and B subunits of ESCRT-I are functional modules that bind in vitro to liposomes containing acidic lipids depending on negative charge density. The MABP domain is capable of autonomously localizing to subcellular puncta and to the plasma membrane. The 1.3-Å atomic resolution crystal structure of the MVB12B MABP domain reveals a β-prism fold, a hydrophobic membrane-anchoring loop, and an electropositive phosphoinositide-binding patch. The basic patch is open, which explains how it senses negative charge density but lacks stereoselectivity. These observations show how ESCRT-I could act as a coincidence detector for acidic phospholipids and protein ligands, enabling it to function both in protein transport at endosomes and in cytokinesis and viral budding at the plasma membrane.HIV | protein structure | protein-membrane interactions | X-ray crystallography | subcellular localization T he concept of modular membrane-targeting domains is an important theme in the architecture of regulatory proteins and central to our current understanding of the subcellular localization of proteins (1-3). The best known of these modules include the PH, PX, FYVE, C1, C2, and ENTH domains (1-3). Each of these domains was initially proposed on the basis of bioinformatics analysis and subsequently confirmed by structural, biochemical, and cell biological approaches.A recent bioinformatics analysis (4) led to the identification of a putative membrane-targeted domain, termed the "MVB12-associated β-prism" (MABP) domain (4). MABP domains are found at the N termini of MVB12A and B, which are subunits of the human ESCRT-I complex (5). ESCRT complexes are responsible for the endosomal sorting of ubiquitinated membrane proteins into multivesicular bodies (MVBs) en route to their lysosomal degradation (6, 7). ESCRT-I in particular is also involved in plasma membrane functions in cytokinesis and the release of HIV-1 and other viruses (8). MABP domains are also found in many membrane-associated bacterial proteins and in the N-terminal region of human DENND4 isoforms. DENND4 proteins are Rab10 guanine nucleotide exchange factors that localize to a tubular Golgi-proximal membrane compartment (9).We set out to test the inference that MABP domains interact with membranes and found that the MVB12A and B MABP domains did. The crystal structure, solved at atomic resolution, showed that the MABP domain has a β-prism fold, consistent with the bioinformatics analysis. The structure identified a potential membrane-binding site, which we confirmed experimentally in vitro and in vivo. We found that the domain bound to liposomes according to the negative charge density of the membrane but with little specificity for particular lipid head groups. We went on to characterize the...

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Illuminating the membrane contact sites between the endoplasmic reticulum and the trans‐Golgi network

2019

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Membrane contact sites (MCSs) between different organelles have been identified and extensively studied over the last decade. Several classes of MCSs have now well‐established roles, although the contacts between the endoplasmic reticulum (ER) and the trans‐side of the Golgi network (TGN) have long remained elusive. Until recently, the study of ER–TGN contact sites has represented a major challenge in the field, as a result of the lack of suitable visualization and isolation techniques. Only in the last 5 years has the combination of advanced technologies and innovative approaches permitted the identification of new molecular players and the functions of ER–TGN MCSs that couple lipid metabolism and anterograde transport. Although much has yet to be discovered, it is now established that ER–TGN MCSs control phosphatidyl‐4‐phosphate homeostasis by coupling the cis and the trans activity of the ER‐resident 4‐phosphatase Sac1. In this review, we focus on recent advances on the composition and function of ER–TGN MCSs.

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High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine

Abstract: Phosphatidylserine exists lumenally in the ER, Golgi, and mitochondria but cytoplasmically in the trans-Golgi and at the plasma membrane, which suggests that functionally important flipping may occur during trafficking.

Cited by 259 publications

References 62 publications

Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling

Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling

Structural basis for membrane targeting by the MVB12-associated β-prism domain of the human ESCRT-I MVB12 subunit

Illuminating the membrane contact sites between the endoplasmic reticulum and the trans‐Golgi network

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