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. 2021 Dec 9;12:7171. doi: 10.1038/s41467-021-27475-2

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — a A 2:1 interaction of PTCH1:pShhNc represents the active signalling complex. The pShhNc lipid appendages insert to seal channels in PTCH1-B. b HHIP-C targets the conserved high-affinity metal ion-binding site on the pShhNc surface (‘protein-protein interaction’), competing with binding from PTCH1-A and other co-receptors, whilst HHIP-N is able to contribute to this by targeting the C-terminal cholesterol moiety, possibly re-establishing PTCH1 cholesterol transport ability. It is also of note that HH signalling is activated via SMO CRD-cholesterol interaction, and competition of this by the HHIP-N CRD represents a possible additional mode of inhibition. Additionally, HHIP-mediated receptor endocytosis may act to remove SHH from the cell surface. c Cell surface GAG-mediated clustering represents a second modality for HH regulation by HHIP. The avidity of HHIP is increased by cluster formation at the proteoglycan layer, similar to how SHH lipoprotein multimers act to increase local morphogen concentration. The GAG-binding site in HHIP-N is also important for this process.