Synthesis and Cellular Labeling of Multifunctional Phosphatidylinositol Bis‐ and Trisphosphate Derivatives

Mueller, Robert; Kojic, Ana; Citir, Mevlut; Schultz, Carsten

doi:10.1002/anie.202103599

Cited by 22 publications

(30 citation statements)

References 40 publications

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“…To increase the spatial resolution of this approach, coumarin-caged derivatives of membrane-permeant phosphoinositides have been generated that enable their light-induced activation via uncaging at specific subcellular sites 222 , 223 . The functionalization of the acyl chain with a diazirine group for UV crosslinking and a terminal alkyne for click chemistry has further expanded the possible applications of membrane-permeant phosphoinositides (for example, to allow the identification of novel phosphoinositide-associated proteins 224 ).…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositides as membrane organizers

Posor

Jang

Haucke

2022

Nat Rev Mol Cell Biol

210

128

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Phosphoinositides are signalling lipids derived from phosphatidylinositol, a ubiquitous phospholipid in the cytoplasmic leaflet of eukaryotic membranes. Initially discovered for their roles in cell signalling, phosphoinositides are now widely recognized as key integrators of membrane dynamics that broadly impact on all aspects of cell physiology and on disease. The past decade has witnessed a vast expansion of our knowledge of phosphoinositide biology. On the endocytic and exocytic routes, phosphoinositides direct the inward and outward flow of membrane as vesicular traffic is coupled to the conversion of phosphoinositides. Moreover, recent findings on the roles of phosphoinositides in autophagy and the endolysosomal system challenge our view of lysosome biology. The non-vesicular exchange of lipids, ions and metabolites at membrane contact sites in between organelles has also been found to depend on phosphoinositides. Here we review our current understanding of how phosphoinositides shape and direct membrane dynamics to impact on cell physiology, and provide an overview of emerging concepts in phosphoinositide regulation.

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Section: Introductionmentioning

confidence: 99%

Phosphoinositides as membrane organizers

Posor

Jang

Haucke

2022

Nat Rev Mol Cell Biol

210

128

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“…In addition to investigating the interaction of a targeted protein with a defined lipid, this chemical toolbox has also been used to perform chemoproteomics studies of protein-lipid interactions in living cells. [196][197][198][199][200][201] In the field of virus research, photoactivatable lipids have been only recently used to demonstrate that the gp41 subunit of Env specifically interacts with chol in the viral membrane via determinants in its CT and that this interaction drives Env clustering, [109] and to study the specific interaction of the IAV HA fusion protein with viral membrane chol via a cholesterol consensus motif. [116] Recently, a similar photoaffinity strategy has been applied to investigate HIV-1 matrix-phosphatidylinositol bisphosphate (PIP 2 ) interaction in the viral membrane.…”

Section: Discussionmentioning

confidence: 99%

Role of Protein–Lipid Interactions in Viral Entry

et al. 2022

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description, lipid raft has generated equal levels of enthusiasm and controversy in the research community. [1,5] This controversy arises from the lack of suitable tools to unravel the existence of such nanostructures in living organisms at resting state. [5][6][7] Despite this long-lasting controversy, what we can ascertain is that the alteration of membrane physicochemical properties such as curvature, elasticity, or fluidity can have a direct effect in membrane protein properties and function, and finally, in viral infectivity. [8,9] Therefore, viruses are a clear example of how cell membrane physicochemical properties are of high evolutionary relevance, as they are exploited by these pathogens in the infection cycle.Viruses are obligatory intracellular parasites that are simple in structure and compositions but hijack the host cellular mechanisms to ensure viral infection and progression. Naked viruses contain a genome encased in a protein shell called capsid, which in the case of enveloped viruses is surrounded by a host cell-derived lipid membrane.The viral entry process is a complex and determinant step necessary for establishing viral infection since viral replication occurs exclusively inside the host cell. It compiles sequential events starting from viral attachment to the host cell to penetration to cell cytoplasm. Attachment of virus particles to host cell molecules that act as cellular receptors, such as lipid or proteins, determines cellular tropism and, therefore, specificity. After adhesion, virus penetration occurs either at the plasma membrane or the endomembrane system upon environment acidification. For enveloped viruses, transfer is achieved by fusion of the viral and cellular membranes. The fusion event is catalyzed by the fusion protein, which engages to receptor(s) triggering a conformational change necessary to induce fusion between both membranes. This conformational change can occur in the plasma membrane at neutral pH or in the endosomal membranes upon endosome acidification. In the case of naked viruses, endosome acidification is needed to trigger conformational changes of the viral protein required in order to transiently destabilize the target membrane without compromising its overall integrity. [10][11][12] Virus entry is not a passive process, since productive entry, and downstream events rely on normal cellular processes including endocytosis (clathrin-mediated, clathrin-independent pathway, raft-dependent pathways, and macropinocytosis), vesicular trafficking, and membrane fusion, all of which involve dynamic membrane processes. [10,13] The fact that lipid interactions, including membrane envelopment, membrane fusion, and membrane remodeling are crucial for successful replication of many viruses triggered studies on compounds that either affect lipid biosynthesis,The viral entry consists of several sequential events that ensure the attachment of the virus to the host cell and the introduction of its genetic material for the continuation of the replication cycle. Both cellular an...

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“…Such probes allow successive light-regulated liberation (or “uncaging” at 400 nm) and photo-cross-linking (at 350 nm). For example, PIPs were installed with coumarin as the photocage . As PIPs have short half-lives, temporal control of probe delivery and activation is crucial.…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Bifunctional Lipid-Derived Affinity-Based Probes (AfBPs) for Analysis of Lipid–Protein Interactome

Yao

2022

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS:Although lipids are not genetically encoded, they are fundamental building blocks of cell membranes and essential components of cell metabolites. Lipids regulate various biological processes, including energy storage, membrane trafficking, signal transduction, and protein secretion; therefore, their metabolic imbalances cause many diseases. Approximately 47 000 lipid species with diverse structures have been identified, but little is known about their crucial roles in cellular systems. Particularly the structural, metabolic, and signaling functions of lipids often arise from interactions with proteins. Lipids attach to proteins not only by covalent bonds but also through noncovalent interactions, which also influence protein functions and localization. Therefore, it is important to explore this lipid−protein "interactome" to understand its roles in health and disease, which may further provide insight for medicinal development. However, lipid structures are generally quite complicated, rendering the systematic characterization of lipid−protein interactions much more challenging.Chemoproteomics is a well-known chemical biology platform in which small-molecule chemical probes are utilized in combination with high-resolution, quantitative mass spectrometry to study protein−ligand interactions in living cells or organisms, and it has recently been applied to the study of protein−lipid interactions as well. The study of these complicated interactions has been advanced by the development of bifunctional lipid probes, which not only enable probes to form covalent cross-links with lipidinteracting proteins under UV irradiation, but are also capable of enriching these proteins through bioorthogonal reactions.In this Account, we will discuss recent developments in bifunctional lipid-derived, affinity-based probes (Af BP)s that have been developed to investigate lipid−protein interactions in live cell systems. First, we will give a brief introduction of fundamental techniques based on Af BPs which are related to lipid research. Then, we will focus on three aspects, including probes developed on the basis of lipidation, lipid-derived probes with different modification positions (e.g., hydrophobic or hydrophilic parts of a lipid), and, finally, in situ biosynthesis of probes through intrinsic metabolic pathways by using chemically modified building blocks. We will present some case studies to describe these probes' design principles and cellular applications. At the end, we will also highlight key limitations of current approaches so as to provide inspirations for future improvement. The lipid probes that have been constructed are only the tip of the iceberg, and there are still plenty of lipid species that have yet to be explored. We anticipate that Af BP-based chemoproteomics and its further advancement will pave the way for a deep understanding of lipid−protein interactions in the future.

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Synthesis and Cellular Labeling of Multifunctional Phosphatidylinositol Bis‐ and Trisphosphate Derivatives

Cited by 22 publications

References 40 publications

Phosphoinositides as membrane organizers

Phosphoinositides as membrane organizers

Role of Protein–Lipid Interactions in Viral Entry

Bifunctional Lipid-Derived Affinity-Based Probes (AfBPs) for Analysis of Lipid–Protein Interactome

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