Article abstract
Nature Structural & Molecular Biology 16, 691 - 697 (2009)
Published online: 28 June 2009 | doi:10.1038/nsmb.1632
The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling
Ivan Bosanac1,4, Henry R Maun2,4, Suzie J Scales3, Xiaohui Wen3, Andreas Lingel2, J Fernando Bazan2, Frederic J de Sauvage3, Sarah G Hymowitz1 & Robert A Lazarus2
Abstract
Hedgehog (Hh) signaling is crucial for many aspects of embryonic development, whereas dysregulation of this pathway is associated with several types of cancer. Hedgehog-interacting protein (Hhip) is a surface receptor antagonist that is equipotent against all three mammalian Hh homologs. The crystal structures of human HHIP alone and bound to Sonic hedgehog (SHH) now reveal that HHIP is comprised of two EGF domains and a six-bladed 
-propeller domain. In the complex structure, a critical loop from HHIP binds the pseudo active site groove of SHH and directly coordinates its Zn2+ cation. Notably, sequence comparisons of this SHH binding loop with the Hh receptor Patched (Ptc1) ectodomains and HHIP- and PTC1-peptide binding studies suggest a 'patch for Patched' at the Shh pseudo active site; thus, we propose a role for Hhip as a structural decoy receptor for vertebrate Hh.
- Department of Structural Biology, Genentech, Inc., South San Francisco, California, USA.
- Department of Protein Engineering, Genentech, Inc., South San Francisco, California, USA.
- Department of Molecular Biology, Genentech, Inc., South San Francisco, California, USA.
- These authors contributed equally to this work.
Correspondence to: Frederic J de Sauvage3 e-mail: sauvage@gene.com
Correspondence to: Sarah G Hymowitz1 e-mail: hymowitz@gene.com
Correspondence to: Robert A Lazarus2 e-mail: laz@gene.com
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