Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1

Gahloth, Deepankar; Levy, Colin; Heaven, Graham; Stefani, Flavia; Wunderley, Lydia; Mould, A. Paul; Cliff, Matthew J.; Bella, Jordi; Fielding, Alistair J.; Woodman, Philip; Tabernero, Lydia

doi:10.1016/j.str.2016.10.006

Cited by 23 publications

(30 citation statements)

References 44 publications

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“…HD-PTP is a multidomain protein ( Figure 1 A). Its minimal functional region includes the first two domains ( Doyotte et al., 2008 ); Bro1 and the coiled coil (CC) that adopts an extended conformation ( Gahloth et al., 2016 ). An HD-PTP Bro1-CC construct was used as bait in a yeast two-hybrid (Y2H) screen to identify new interacting partners of HD-PTP that could be relevant to ESCRT function on the endocytic pathway.…”

Section: Resultsmentioning

confidence: 99%

Structural Basis for Specific Interaction of TGFβ Signaling Regulators SARA/Endofin with HD-PTP

et al. 2017

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SummarySARA 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-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 TGFβ/BMP signaling is controlled.

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Section: Resultsmentioning

confidence: 99%

Structural Basis for Specific Interaction of TGFβ Signaling Regulators SARA/Endofin with HD-PTP

et al. 2017

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“…Linking PTPN23 and BICD1 to endocytic sorting of NTRs is mechanistically challenging in light of the functional heterogeneity of signalling endosomes (Villarroel-Campos et al, 2018) and the emerging differences in how this process is regulated in post-mitotic neurons versus proliferating cells. Although further work is necessary to fully characterise the PTPN23-KD phenotype described here, the role of PTPN23 in intracellular cargo sorting is somewhat easier to interpret than how BICD1 performs this function, primarily due to the extensive literature focussed on the characterisation of PTPN23 in EGFR dynamics (Woodman, 2016;Gahloth et al, 2016Gahloth et al, , 2017Tabernero and Woodman, 2018). Interestingly, PTPN23 binds endophilin A1 (Ichioka et al, 2007), which is involved in the endocytic sorting of TrkB (Burk et al, 2017).…”

Section: Discussionmentioning

confidence: 98%

PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors

Budzinska

Villarroel‐Campos

Golding

et al. 2020

Journal of Cell Science

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Signalling by target-derived neurotrophins is essential for the correct development of the nervous system and its maintenance throughout life. Several aspects concerning the lifecycle of neurotrophins and their receptors have been characterised over the years, including the formation, endocytosis and trafficking of signalling-competent ligandreceptor complexes. However, the molecular mechanisms directing the sorting of activated neurotrophin receptors are still elusive. Previously, our laboratory identified Bicaudal-D1 (BICD1), a dynein motor adaptor, as a key factor for lysosomal degradation of brain-derived neurotrophic factor (BDNF)-activated TrkB (also known as NTRK2) and p75 NTR (also known as NGFR) in motor neurons. Here, using a proteomics approach, we identified protein tyrosine phosphatase, non-receptor type 23 (PTPN23), a member of the endosomal sorting complexes required for transport (ESCRT) machinery, in the BICD1 interactome. Molecular mapping revealed that PTPN23 is not a canonical BICD1 cargo; instead, PTPN23 binds the N-terminus of BICD1, which is also essential for the recruitment of cytoplasmic dynein. In line with the BICD1-knockdown phenotype, loss of PTPN23 leads to increased accumulation of BDNF-activated p75 NTR and TrkB in swollen vacuolelike compartments, suggesting that neuronal PTPN23 is a novel regulator of the endocytic sorting of neurotrophin receptors.

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“…Its C-terminal ubiquitin-binding region (SOUBA; solenoid of overlapping UBAs) [ 68 ] is essential for cargo trafficking [ 63 ]. UBAP1 binds to the conserved FYx 2 L motif within the coiled-coil domain of HD-PTP ( Figure 4 ), but cannot bind Alix [ 69 ]. This binding selectivity is determined, in part, by the overall shape of each coiled-coil domain, which in HD-PTP adopts an open and extended conformation, and by local amino acid sequence differences within the respective FYx 2 L-binding pockets [ 69 ].…”

Section: Escrts and Egfr Sorting To The Mvbmentioning

confidence: 99%

“…UBAP1 binds to the conserved FYx 2 L motif within the coiled-coil domain of HD-PTP ( Figure 4 ), but cannot bind Alix [ 69 ]. This binding selectivity is determined, in part, by the overall shape of each coiled-coil domain, which in HD-PTP adopts an open and extended conformation, and by local amino acid sequence differences within the respective FYx 2 L-binding pockets [ 69 ]. ESCRT-I also engages HD-PTP via TSG101 binding to the PRR [ 70 ], at a site that overlaps with that for the STAM2 SH3 domain [ 54 ].…”

Section: Escrts and Egfr Sorting To The Mvbmentioning

confidence: 99%

Dissecting the role of His domain protein tyrosine phosphatase/PTPN23 and ESCRTs in sorting activated epidermal growth factor receptor to the multivesicular body

Tabernero

Woodman

2018

Biochemical Society Transactions

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Sorting of activated epidermal growth factor receptor (EGFR) into intraluminal vesicles (ILVs) within the multivesicular body (MVB) is an essential step during the down-regulation of the receptor. The machinery that drives EGFR sorting attaches to the cytoplasmic face of the endosome and generates vesicles that bud into the endosome lumen, but somehow escapes encapsulation itself. This machinery is termed the ESCRT (endosomal sorting complexes required for transport) pathway, a series of multi-protein complexes and accessory factors first identified in yeast. Here, we review the yeast ESCRT pathway and describe the corresponding components in mammalian cells that sort EGFR. One of these is His domain protein tyrosine phosphatase (HD-PTP/PTPN23), and we review the interactions involving HD-PTP and ESCRTs. Finally, we describe a working model for how this ESCRT pathway might overcome the intrinsic topographical problem of EGFR sorting to the MVB lumen.

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Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1

Cited by 23 publications

References 44 publications

Structural Basis for Specific Interaction of TGFβ Signaling Regulators SARA/Endofin with HD-PTP

Structural Basis for Specific Interaction of TGFβ Signaling Regulators SARA/Endofin with HD-PTP

PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors

Dissecting the role of His domain protein tyrosine phosphatase/PTPN23 and ESCRTs in sorting activated epidermal growth factor receptor to the multivesicular body

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