Interactions between Hedgehog proteins and their binding partners come into view

Philip A. Beachy; Sarah G. Hymowitz; Robert A. Lazarus; Daniel J. Leahy; Christian Siebold

doi:10.1101/gad.1951710

Interactions between Hedgehog proteins and their binding partners come into view

¹Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA;
²Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA;
³Department of Structural Biology, Genentech, South San Francisco, California 94080, USA;
⁴Department of Protein Engineering, Genentech, South San Francisco, California 94080, USA;
⁵Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
⁶Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom

Abstract

Hedgehog (Hh) proteins are secreted signaling molecules that mediate essential tissue-patterning events during embryonic development and function in tissue homeostasis and regeneration throughout life. Hh signaling is regulated by multiple mechanisms, including covalent lipid modification of the Hh protein and interactions with multiple protein and glycan partners. Unraveling the nature and effects of these interactions has proven challenging, but recent structural and biophysical studies of Hh proteins and active fragments of heparin, Ihog, Cdo, Boc, Hedgehog-interacting protein (Hhip), Patched (Ptc), and the monoclonal antibody 5E1 have added a new level of molecular detail to our understanding of how Hh signal response and distribution are regulated within tissues. We review these results and discuss their implications for understanding Hh signaling in normal and disease states.