Development of isotope-enriched phosphatidylinositol-4- and 5-phosphate cellular mass spectrometry probes

Joffrin, Amélie M; Saunders, Alex M.; Barneda, David; Flemington, Vikki; Thompson, Amber L.; Sanganee, Hitesh J.; Conway, Stuart J.

doi:10.1039/d0sc06219g

Cited by 5 publications

(5 citation statements)

References 58 publications

(83 reference statements)

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“…Furthermore, there are no methods for targeted manipulation of a specific PI5P species, such as di-C 16:0 PI5P. Chemical biology approaches for derivatizing PI5P ( 68 ) and nuclear injection ( 69 , 70 ) coupled to single-cell analysis might be promising avenues in this regard to deduce the functional role of hUHRF1 regulation by PI5P.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

et al. 2022

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Chromatin marks are recognized by distinct binding modules, many of which are embedded in multidomain proteins. How the different functionalities of such complex chromatin modulators are regulated is often unclear. Here, we delineated the interplay of the H3 amino terminus– and K9me-binding activities of the multidomain hUHRF1 protein. We show that the phosphoinositide PI5P interacts simultaneously with two distant flexible linker regions connecting distinct domains of hUHRF1. The binding is dependent on both, the polar head group, and the acyl part of the phospholipid and induces a conformational rearrangement juxtaposing the H3 amino terminus and K9me3 recognition modules of the protein. In consequence, the two features of the H3 tail are bound in a multivalent, synergistic manner. Our work highlights a previously unidentified molecular function for PI5P outside of the context of lipid mono- or bilayers and establishes a molecular paradigm for the allosteric regulation of complex, multidomain chromatin modulators by small cellular molecules.

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Section: Discussionmentioning

confidence: 99%

Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

et al. 2022

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“…The enzyme systems and putative signaling events controlling nuclear PI5P are complex and difficult to control [56][57][58] . Chemical biology approaches for derivatizing PI5P 59 and nuclear injection 60,61 coupled to single cell analysis might be promising avenues in this regard to deduce the functional role of UHRF1/ PI5P regulation.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of UHRF1 allosteric activation for synergistic histone modification binding by PI5P

Mandal

Yerkesh

Kharchenko

et al. 2021

Preprint

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Chromatin marks are recognized by distinct binding modules many of which are embedded in multidomain proteins or complexes. How the different protein functionalities of complex chromatin modulators are regulated is often unclear. Using a combination of biochemical, biophysical and structural approaches we delineated the regulation of the H3unmodified and H3K9me binding activities of the multidomain UHRF1 protein. The phosphoinositide PI5P interacts with two distant flexible linker regions of UHRF1 in a mode that is dependent on the polar head group and the acyl part of the phospholipid. The associated conformational rearrangements stably position the H3unmodified and H3K9me3 histone recognition modules of UHRF1 for multivalent and synergistic binding of the H3 tail. Our work highlights a novel molecular function for PI5P outside of the context of lipid mono- or bilayers and establishes a molecular paradigm for the allosteric regulation of complex, multidomain chromatin modulators by small cellular molecules.

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“…in his postdoctoral studies 21 and independent career. 22 This works demonstrates that interdisciplinary nature of Shaomeng's work, combing computational approaches with complex synthesis, to probe the biological function and medicinal applications of these compounds.…”

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confidence: 92%

Celebrating the Medicinal Chemistry of Gunda Georg and Shaomeng Wang

Bolognesi¹,

Conway²

2021

J. Med. Chem.

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Development of isotope-enriched phosphatidylinositol-4- and 5-phosphate cellular mass spectrometry probes

Abstract: We report the synthesis of deuterium-labelled derivatives of phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, and demonstrate their use in quantifying levels of endogenous phospholipids in cells.

Cited by 5 publications

References 58 publications

Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

Molecular basis of UHRF1 allosteric activation for synergistic histone modification binding by PI5P

Celebrating the Medicinal Chemistry of Gunda Georg and Shaomeng Wang

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