Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling

Samuel C. Griffiths, Rebekka A. Schwab, Kamel El Omari, Benjamin Bishop, Ellen J. Iverson, Tomas Malinauskas, Ramin Dubey, Mingxing Qian, Douglas F. Covey, Robert J.C. Gilbert, Rajat Rohatgi, Christian Siebold

Research output: Contribution to journalArticlepeer-review

Abstract

Hedgehog (HH) morphogen signalling, crucial for cell growth and tissue patterning in animals, is initiated by the binding of dually lipidated HH ligands to cell surface receptors. Hedgehog-Interacting Protein (HHIP), the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling, binds directly to SHH with high nanomolar affinity, sequestering SHH. Here, we report the structure of the HHIP N-terminal domain (HHIP-N) in complex with a glycosaminoglycan (GAG). HHIP-N displays a unique bipartite fold with a GAG-binding domain alongside a Cysteine Rich Domain (CRD). We show that HHIP-N is required to convey full HHIP inhibitory function, likely by interacting with the cholesterol moiety covalently linked to HH ligands, thereby preventing this SHH-attached cholesterol from binding to the HH receptor Patched (PTCH1). We also present the structure of the HHIP C-terminal domain in complex with the GAG heparin. Heparin can bind to both HHIP-N and HHIP-C, thereby inducing clustering at the cell surface and generating a high-avidity platform for SHH sequestration and inhibition. Our data suggest a multimodal mechanism, in which HHIP can bind two specific sites on the SHH morphogen, alongside multiple GAG interactions, to inhibit SHH signalling.

Original languageEnglish
Article number7171
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

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