5mk0

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Crystal structure of the His Domain Protein Tyrosine Phosphatase (HD-PTP/PTPN23) Bro1 domain (Endofin peptide complex)Crystal structure of the His Domain Protein Tyrosine Phosphatase (HD-PTP/PTPN23) Bro1 domain (Endofin peptide complex)

Structural highlights

5mk0 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:PTPN23, KIAA1471 (HUMAN)
Activity:Protein-tyrosine-phosphatase, with EC number 3.1.3.48
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PTN23_HUMAN] Plays a role in sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs) via its interaction with the ESCRT-I complex (endosomal sorting complex required for transport I), and possibly also other ESCRT complexes. May act as a negative regulator of Ras-mediated mitogenic activity. Plays a role in ciliogenesis.[1] [2] [3] [ZFY16_HUMAN] May be involved in regulating membrane trafficking in the endosomal pathway. Overexpression induces endosome aggregation. Required to target TOM1 to endosomes.[4] [5]

Publication Abstract from PubMed

SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated transforming growth factor beta/bone morphogenetic protein (TGFbeta/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-PTPBro1 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 TGFbeta/BMP signaling is controlled.

Structural Basis for Specific Interaction of TGFbeta Signaling Regulators SARA/Endofin with HD-PTP.,Gahloth D, Levy C, Walker L, Wunderley L, Mould AP, Taylor S, Woodman P, Tabernero L Structure. 2017 Jul 5;25(7):1011-1024.e4. doi: 10.1016/j.str.2017.05.005. Epub, 2017 Jun 8. PMID:28602823[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Doyotte A, Mironov A, McKenzie E, Woodman P. The Bro1-related protein HD-PTP/PTPN23 is required for endosomal cargo sorting and multivesicular body morphogenesis. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6308-13. doi:, 10.1073/pnas.0707601105. Epub 2008 Apr 23. PMID:18434552 doi:http://dx.doi.org/10.1073/pnas.0707601105
  2. ↑ Kim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K, Ideker T, Aza-Blanc P, Gleeson JG. Functional genomic screen for modulators of ciliogenesis and cilium length. Nature. 2010 Apr 15;464(7291):1048-51. doi: 10.1038/nature08895. PMID:20393563 doi:10.1038/nature08895
  3. ↑ Stefani F, Zhang L, Taylor S, Donovan J, Rollinson S, Doyotte A, Brownhill K, Bennion J, Pickering-Brown S, Woodman P. UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting. Curr Biol. 2011 Jul 26;21(14):1245-50. doi: 10.1016/j.cub.2011.06.028. Epub 2011 , Jul 14. PMID:21757351 doi:http://dx.doi.org/10.1016/j.cub.2011.06.028
  4. ↑ Seet LF, Hong W. Endofin, an endosomal FYVE domain protein. J Biol Chem. 2001 Nov 9;276(45):42445-54. Epub 2001 Sep 6. PMID:11546807 doi:http://dx.doi.org/10.1074/jbc.M105917200
  5. ↑ Seet LF, Liu N, Hanson BJ, Hong W. Endofin recruits TOM1 to endosomes. J Biol Chem. 2004 Feb 6;279(6):4670-9. Epub 2003 Nov 12. PMID:14613930 doi:http://dx.doi.org/10.1074/jbc.M311228200
  6. ↑ Gahloth D, Levy C, Walker L, Wunderley L, Mould AP, Taylor S, Woodman P, Tabernero L. Structural Basis for Specific Interaction of TGFbeta Signaling Regulators SARA/Endofin with HD-PTP. Structure. 2017 Jul 5;25(7):1011-1024.e4. doi: 10.1016/j.str.2017.05.005. Epub, 2017 Jun 8. PMID:28602823 doi:http://dx.doi.org/10.1016/j.str.2017.05.005

5mk0, resolution 1.77Å

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