5MK3

Crystal structure of the His Domain Protein Tyrosine Phosphatase (HD-PTP/PTPN23) Bro 1 domain (CHMP4C peptide complex structure)

Summary for 5MK3

• Entry DOI: 10.2210/pdb5mk3/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 23, Charged multivesicular body protein 4c (3 entities in total)
• Functional Keywords: escrt-iii chmp4c, hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: Q9H3S7; Cytoplasm, cytosol: Q96CF2
• Total number of polymer chains: 8
• Total formula weight: 171244.53

Authors

Levy, C. (deposition date: 2016-12-02, release date: 2017-08-16, Last modification date: 2024-01-17)

Primary citation

Gahloth, D.,Levy, C.,Walker, L.,Wunderley, L.,Mould, A.P.,Taylor, S.,Woodman, P.,Tabernero, L.
Structural Basis for Specific Interaction of TGF beta Signaling Regulators SARA/Endofin with HD-PTP.
Structure, 25:1011-1024.e4, 2017

PubMed 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.

PubMed: 28602823
DOI: 10.1016/j.str.2017.05.005

Experimental method

X-RAY DIFFRACTION (2 Å)