Spectrin binding motifs regulate Scribble cortical dynamics and polarity function
| Autor: | Batiste Boëda, Sandrine Etienne-Manneville |
|---|---|
| Přispěvatelé: | Polarité cellulaire, Migration et Cancer - Cell Polarity, Migration and Cancer, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Institut National du Cancer, l'Association pour la Recherche contre le Cancer, and La Ligue contre le Cancer. B Boëda is supported by Institut National de la Santé et de la Recherche Médicale., We are grateful to JP Borg, Norbert Frey and A El Amraoui for plasmids and thank Jean-Yves Tinevez from the Plate-Forme d'Imagerie Dynamique/Imagopole of Institut Pasteur for technical support., Lemesle, Marie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
MESH: Sequence Homology
Amino Acid Amino Acid Motifs MESH: Amino Acid Sequence MESH: Amino Acid Motifs 0302 clinical medicine Cell polarity cell biology Spectrin polarity cortical cytoskeleton Biology (General) Genetics 0303 health sciences General Neuroscience Cell Polarity MESH: Spectrin General Medicine 3. Good health Cell biology spina bifida 030220 oncology & carcinogenesis Medicine MESH: Membrane Proteins MESH: Cell Polarity SCRIB QH301-705.5 Science Molecular Sequence Data Short Report Biology General Biochemistry Genetics and Molecular Biology Cell Line Protein–protein interaction 03 medical and health sciences Cell cortex Humans biochemistry cancer MESH: Tumor Suppressor Proteins Amino Acid Sequence human mouse 030304 developmental biology Binding Sites MESH: Humans MESH: Molecular Sequence Data Sequence Homology Amino Acid General Immunology and Microbiology Tumor Suppressor Proteins Membrane Proteins Cortical actin cytoskeleton MESH: Cell Line protein–protein interaction Membrane protein MESH: Binding Sites [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie Spectrin binding |
| Zdroj: | eLife eLife, 2015, 4, pp.e04726. ⟨10.7554/eLife.04726⟩ eLife, eLife Sciences Publication, 2015, 4, pp.e04726. ⟨10.7554/eLife.04726⟩ eLife, Vol 4 (2015) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.04726⟩ |
| Popis: | The tumor suppressor protein Scribble (SCRIB) plays an evolutionary conserved role in cell polarity. Despite being central for its function, the molecular basis of SCRIB recruitment and stabilization at the cell cortex is poorly understood. Here we show that SCRIB binds directly to the CH1 domain of β spectrins, a molecular scaffold that contributes to the cortical actin cytoskeleton and connects it to the plasma membrane. We have identified a short evolutionary conserved peptide motif named SADH motif (SCRIB ABLIMs DMTN Homology) which is necessary and sufficient to mediate protein interaction with β spectrins. The SADH domains contribute to SCRIB dynamics at the cell cortex and SCRIB polarity function. Furthermore, mutations in SCRIB SADH domains associated with spina bifida and cancer impact the stability of SCRIB at the plasma membrane, suggesting that SADH domain alterations may participate in human pathology. DOI: http://dx.doi.org/10.7554/eLife.04726.001 eLife digest Proteins found in cells often have more than one role. Scribble is one such multi-tasking protein that is found in a diverse range of species, including fruit flies and humans. Although Scribble commonly helps to ensure that the components of a cell are in their correct locations, its exact roles vary between species. To perform its role well, Scribble itself must localize to the cell cortex—the inside surface of the cell membrane—at the regions where cells connect to one another. How this localization occurs is not fully understood; and defects in the human form of Scribble have been linked to diseases including spina bifida and cancer. Much of the Scribble protein is very similar across different species, but the fruit fly and human version of the protein have large differences in their ‘C-terminal region’ that makes up one end of each protein. Boëda and Etienne-Manneville now show that in humans and other animals with backbones—but not in fruit flies—the C-terminal region of Scribble contains three repeats of a sequence called the SADH motif. These motifs can bind to proteins called beta spectrins, which connect the cell's outer membrane to the scaffolding-like structure inside the cell that provides support. Mutations that alter the SADH motif interfere with Scribble's ability to bind to the scaffolding, and alters Scribble localization at cell–cell contacts or the cell cortex. Boëda and Etienne-Manneville also found that some mutations linked to spina bifida and cancer affect the SADH motif, suggesting that this motif has a wider role in disease. While the abnormal localization of Scribble inside cells is frequently observed in particularly difficult to survive cancers, the molecular mechanism that causes Scribble to fail to localize to the cell periphery is still poorly understood. Boëda and Etienne-Manneville's work establishes the beta spectrin family of proteins as regulators that stabilize Scribble at the cell cortex and suggests that Scribble-associated diseases might depend on the integrity of the spectrin network. DOI: http://dx.doi.org/10.7554/eLife.04726.002 |
| Databáze: | OpenAIRE |
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