AI Article Synopsis
- SARA and endofin are proteins that help activate Smad phosphorylation through TGFβ/BMP receptors and also recruit the tumor suppressor HD-PTP, which is crucial for sorting and regulating these receptors.
- The research shows that SARA and endofin have high-affinity interactions with HD-PTP, specifically at a unique binding site that differs from how HD-PTP interacts with other proteins like CHMP4.
- The study uses crystal structures and mutagenesis to illustrate the specific binding mechanisms of SARA/endofin to HD-PTP, providing insights into how TGFβ/BMP signaling is regulated through endocytosis.
Article Abstract
SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) receptors. We show in this study that SARA and endofin also recruit the tumor supressor HD-PTP, a master regulator of endosomal sorting and ESCRT-dependent receptor downregulation. High-affinity interactions occur between the SARA/endofin N termini, and the conserved hydrophobic region in the HD-PTP Bro1 domain that binds CHMP4/ESCRT-III. CHMP4 engagement is a universal feature of Bro1 proteins, but SARA/endofin binding is specific to HD-PTP. Crystallographic structures of HD-PTP in complex with SARA, endofin, and three CHMP4 isoforms revealed that all ligands bind similarly to the conserved site but, critically, only SARA/endofin interact at a neighboring pocket unique to HD-PTP. The structures, together with mutagenesis and binding analysis, explain the high affinity and specific binding of SARA/endofin, and why they compete so effectively with CHMP4. Our data invoke models for how endocytic regulation of TGFβ/BMP signaling is controlled.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501724 | PMC |
| http://dx.doi.org/10.1016/j.str.2017.05.005 | DOI Listing |
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Article Synopsis
- SARA and endofin are proteins that help activate Smad phosphorylation through TGFβ/BMP receptors and also recruit the tumor suppressor HD-PTP, which is crucial for sorting and regulating these receptors.
- The research shows that SARA and endofin have high-affinity interactions with HD-PTP, specifically at a unique binding site that differs from how HD-PTP interacts with other proteins like CHMP4.
- The study uses crystal structures and mutagenesis to illustrate the specific binding mechanisms of SARA/endofin to HD-PTP, providing insights into how TGFβ/BMP signaling is regulated through endocytosis.
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