Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm

Qian, Hui‐Fen; Cao, Pingping; Hu, Miaohui; Gao, Shuai; Yan, Nieng; Gong, Xin

doi:10.1101/461491

Cited by 4 publications

(2 citation statements)

References 52 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, P75Q, K181T and F549C alter amino acids in the luminal domains. Using Phyre 2 to align the sequence for PTCHD1 with that of human NPC1 and Ptch1, whose 3D structures have been determined previously (11, 20–22, 25, 26), we used PyMol to generate a hypothetical three-dimensional structure for PTCHD1 ( Figure 1D ). For all regions except the N, ML and C cytoplasmic domains, this predicted model is nearly identical to a recent 3D model predicted using AlphaFold (27) (see Appendix 1).…”

Section: Resultsmentioning

confidence: 99%

Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt N-Glycosylation and Reduce Protein Stability

Xie

Pastore

Vincent

et al. 2022

Preprint

View full text Add to dashboard Cite

PTCHD1 has been implicated in Autism Spectrum Disorders (ASD) and/or intellectual disability, where copy number variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of PTCHD1 have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization and regulation of the PTCHD1 protein are currently unknown. This paucity of data concerning PTCHD1 prevents the effective evaluation of sequence variants identified during diagnostic screening. Here, we characterize PTCHD1 protein binding partners, extending previously reported interactions with postsynaptic scaffolding protein, SAP102. Six rare missense variants of PTCHD1 were also identified from patients with neurodevelopmental disorders. After modelling these variants on a hypothetical three-dimensional structure of PTCHD1, based on the solved structure of NPC1, PTCHD1 variants harbouring these mutations were assessed for protein stability, post-translational processing and protein trafficking. We show here that wild-type PTCHD1 post-translational modification includes complex N-glycosylation and that specific mutant proteins disrupt normal N-link glycosylation processing. However, regardless of their processing, these mutants still localized to PSD95-containing dendritic processes and remained competent for complexing SAP102.

show abstract

Section: Resultsmentioning

confidence: 99%

Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt N-Glycosylation and Reduce Protein Stability

Xie

Pastore

Vincent

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…2B). At the second interface, the N-terminal palmitoyl group and subsequent 15 amino acids of SHH are inserted into the protein core of PTCH, and the C-terminal cholesteroyl moiety of SHH is inserted into ECD1 (Qi et al, 2018b;Qian et al, 2018). Both SHH-attached lipids occlude the putative tunnel that connects the ECD1 and SSD sterol binding sites (PTCH1-mol2 in Fig.…”

Section: How Hh Ligands Inhibit Ptchmentioning

confidence: 99%

Biochemical mechanisms of vertebrate hedgehog signaling

2019

View full text Add to dashboard Cite

Signaling pathways that mediate cell-cell communication are essential for collective cell behaviors in multicellular systems. The hedgehog (HH) pathway, first discovered and elucidated in Drosophila, is one of these iconic signaling systems that plays many roles during embryogenesis and in adults; abnormal HH signaling can lead to birth defects and cancer. We review recent structural and biochemical studies that have advanced our understanding of the vertebrate HH pathway, focusing on the mechanisms by which the HH signal is received by patched on target cells, transduced across the cell membrane by smoothened, and transmitted to the nucleus by GLI proteins to influence gene-expression programs.

show abstract

Cryo-EM structure of the Hedgehog release protein Dispatched

Cannac

Falschlunger

et al. 2019

Preprint

View full text Add to dashboard Cite

AbstractThe Hedgehog signaling pathway controls embryonic development and adult tissue homeostasis in multicellular organisms. In Drosophila melanogaster, the pathway is primed by secretion of a dually lipid-modified morphogen, Hedgehog (Hh), a process dependent on a membrane-integral protein Dispatched. Although Dispatched is a critical component of the pathway, the structural basis of its activity has so far not been described. Here, we describe a cryo-EM structure of the Drosophila melanogaster Dispatched at 3.2 Å resolution. The ectodomains of Dispatched adopt an open conformation suggestive of a receptor-chaperone role. A 3D reconstruction of Dispatched bound to Hh confirms the ability of Dispatched to bind Hh but using a unique mode distinct from those previously observed in structures of Hh complexes. The structure may represent the state of the complex that precedes shedding of Hh from the surface of the morphogen-releasing cell.

show abstract

Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm

Cited by 4 publications

References 52 publications

Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt N-Glycosylation and Reduce Protein Stability

Nonsynonymous Mutations in Intellectual Disability and Autism Spectrum Disorder Gene PTCHD1 Disrupt N-Glycosylation and Reduce Protein Stability

Biochemical mechanisms of vertebrate hedgehog signaling

Cryo-EM structure of the Hedgehog release protein Dispatched

Contact Info

Product

Resources

About