VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites

Subra, Mélody; Dezi, Manuela; Bigay, Joëlle; Lacas‐Gervais, Sandra; Cicco, Aurélie Di; Araújo, Ana Rita Dias; Abélanet, Sophie; Fleuriot, Lucile; Debayle, Delphine; Gautier, Romain; Patel, Amanda; Roussi, Fanny; Antonny, Bruno; Lévy, Daniel; Mesmin, Bruno

doi:10.1016/j.devcel.2022.12.010

Cited by 19 publications

(22 citation statements)

References 70 publications

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“…[ 94 ] VAPA also contains intrinsically disordered regions, which enable versatile tethering at MCS and contribute to membrane tethering plasticity and efficiency. [ 95 ]…”

Section: Regulation Of Mcs By Oligomerization Of Tether Proteinsmentioning

confidence: 99%

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

et al. 2022

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In recent years, membrane contact sites (MCS), which mediate interactions between virtually all subcellular organelles, have been extensively characterized and shown to be essential for intracellular communication. In this review essay, we focus on an emerging topic: the regulation of MCS. Focusing on the tether proteins themselves, we discuss some of the known mechanisms which can control organelle tethering events and identify apparent common regulatory hubs, such as the VAP interface at the endoplasmic reticulum (ER). We also highlight several currently hypothetical concepts, including the idea of tether oligomerization and redox regulation playing a role in MCS formation. We identify gaps in our current understanding, such as the identity of the majority of kinases/phosphatases involved in tether modification and conclude that a holistic approach-incorporating the formation of multiple MCS, regulated by interconnected regulatory modulators-may be required to fully appreciate the true complexity of these fascinating intracellular communication systems.

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“…[ 94 ] VAPA also contains intrinsically disordered regions, which enable versatile tethering at MCS and contribute to membrane tethering plasticity and efficiency. [ 95 ]…”

Section: Regulation Of Mcs By Oligomerization Of Tether Proteinsmentioning

confidence: 99%

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

et al. 2022

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“…MD simulations were performed essentially as described previously (Subra et al, 2023), except that full-length membranous VAP-A and VAP-B proteins were simulated. Simulations of modified VAP-A and VAP-B structures from AlphaFold in a membrane were prepared with CHARMM-GUI using 560 POPC, 560 DOPC, and 56 cholesterol (5% cholesterol), a water thickness of 30 Å at a temperature of 303 K and neutralized with 120 mM NaCl.…”

Section: Methodsmentioning

confidence: 99%

“…Disorder prediction indicates that the inserted sequence is unstructured, thus forming an extra-long flexible linker 1. We have shown that expressing this isoform rescued a range of defects associated with ER/Golgi and ER/mitochondria MCS in VAP-A KO cells (Subra et al, 2023), but the functional implication of this splice variant remains to be determined. As a side note, there is also a splice variant of VAP-B, called VAP-C, whose sequence stops in the middle of the MSP, but its function remains largely unexplored.…”

mentioning

confidence: 96%

“…They encompass a N-terminal major sperm protein (MSP) domain, a central coiled-coil region for dimerization and a C-terminal TM domain (Figure 1A). Two intrinsically disordered regions (linkers 1 and 2) connect these different domains together and ensure VAP flexibility (Subra et al, 2023). VAP-A and VAP-B act as receptors for ∼100 proteins containing a short recognition motif called “two phenylalanines in an acidic tract” (FFAT), which consists of the consensus sequence EFFDAxE ﬂanked by acidic residues (Loewen et al, 2003).…”

mentioning

confidence: 99%

“…Another structural feature worth mentioning is VAP linker regions, which show the most significant sequence variation between VAP-A and VAP-B. In a recent study, we demonstrated that these linkers are responsible for VAP-A flexibility, and are necessary for its engagement in the highly dynamic ER/Golgi MCS (Mora et al, 2021; Subra et al, 2023). By contrast, mutants of VAP-A designed to be more rigid only adapt to ER/Mitochondria MCS, which are more stable over time.…”

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confidence: 99%

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Stranger Twins: A Tale of Resemblance and Contrast Between VAP Proteins

Subra,

Grimanelli,

Gautier

et al. 2023

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When considering the vesicle-associated membrane protein-associated protein (VAP) family, major receptors at the surface of the endoplasmic reticulum (ER), it appears that VAP-A and VAP-B paralogs largely overlap in structure and function, and that specific features to distinguish these two proteins hardly exist or are poorly documented. Here, we question the degree of redundancy between VAP-A and VAP-B: is one simply a backup plan, in case of loss of function of one of the two genes, or are there molecular and functional divergences that would explain their maintenance during evolution?

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Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

Tian,

Andrews,

Yan

et al. 2024

Chronic Diseases and Translational Medicine

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Calcium‐sensing receptor (CaSR), a family C G‐protein‐coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L‐Trp and L‐Phe), small peptides, anions (e.g., HCO3− and PO43−), and pH. CaSR‐mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein–protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+‐dependent cellular physiological processes and in CaSR‐dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G‐protein‐coupled receptors.

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VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites

Cited by 19 publications

References 70 publications

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

Stranger Twins: A Tale of Resemblance and Contrast Between VAP Proteins

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

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