Nanoscale Organization of Hedgehog Is Essential for Long-Range Signaling

Vyas, Neha; Goswami, Debanjan; Manonmani, A.; Sharma, P. L.; Ranganath, H. A.; VijayRaghavan, K.; Shashidhara, L. S.; Sowdhamini, Ramanathan; Mayor, Satyajit

doi:10.1016/j.cell.2008.05.026

Cited by 139 publications

(167 citation statements)

References 39 publications

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“…Furthermore, a recent study has shown that Hh monomers can form nanoscale oligomers that are selectively enriched in visible clusters containing HSPGs [43]. The association of Hh oligomers with HSPG clusters promoted the dispatch of Hh for long-range transport (possibly via lipoprotein particles) and the activation of Hh target-gene expression in distant receiving cells [43]. However, enhanced binding to HS is not a common finding and was not demonstrated for the E131K mutant protein.…”

Section: Discussionmentioning

confidence: 98%

“…Studies have suggested that HSPGs can facilitate Hh movement by means of lipoprotein binding in the extracellular matrix and can antagonize PTC-mediated Hh sequestration, thereby promoting long-range movement [41,42]. Furthermore, a recent study has shown that Hh monomers can form nanoscale oligomers that are selectively enriched in visible clusters containing HSPGs [43]. The association of Hh oligomers with HSPG clusters promoted the dispatch of Hh for long-range transport (possibly via lipoprotein particles) and the activation of Hh target-gene expression in distant receiving cells [43].…”

Section: Discussionmentioning

confidence: 99%

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Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

Xiao

et al. 2011

Cell Res

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Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

Xiao

et al. 2011

Cell Res

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“…ing (23), so it is unlikely that a biologically relevant filament would be incompatible with complex formation with positive regulators of the signaling pathway. The specific crystal lattice contact in the original ShhN structure that was postulated as a possible Hh oligomerization interface involves Arg 73 (Lys 132 in Drosophila HhN) (23). This interface buries only 180 Å 2 of surface area and does not occur in any other HhN-containing crystal structures, either alone or complexed with Ihog, CDOFn3, BOCFn3, or Hip (22,32,36,37) and thus seems unlikely to represent a conserved self-interaction among HhN molecules.…”

Section: Resultsmentioning

confidence: 99%

“…Studies with fluorescently labeled Hh provide evidence for both a "nanoscale" assembly of Hh proteins that depends on homo-oligomerization and a visible-light scale cluster that depends on interactions between Hh and heparin sulfate proteoglycans (23 We find that interactions between mammalian Hh proteins and CDO and BOC are conserved in nature, and systematic inspection of 14 different HhN-containing crystal lattices reveals no evidence for a conserved contact that may reflect a physiological self-interaction between Hh proteins. We also show that interactions between ShhN and CDOFn3 are diminished at low pH, suggesting that CDO and BOC will release bound Hh proteins in low pH environments.…”

mentioning

confidence: 84%

“…In addition to interactions with other binding partners, a potential Hh self-interaction has been identified and suggested to be important for Hh function (23). Studies with fluorescently labeled Hh provide evidence for both a "nanoscale" assembly of Hh proteins that depends on homo-oligomerization and a visible-light scale cluster that depends on interactions between Hh and heparin sulfate proteoglycans (23 We find that interactions between mammalian Hh proteins and CDO and BOC are conserved in nature, and systematic inspection of 14 different HhN-containing crystal lattices reveals no evidence for a conserved contact that may reflect a physiological self-interaction between Hh proteins.…”

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confidence: 99%

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All Mammalian Hedgehog Proteins Interact with Cell Adhesion Molecule, Down-regulated by Oncogenes (CDO) and Brother of CDO (BOC) in a Conserved Manner

Kavran

Ward

Oladosu

et al. 2010

Journal of Biological Chemistry

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These results show that all mammalian Hh proteins bind CDO and BOC in the same manner. We also show that interactions between Hh proteins and CDO are weakened at low pH. Formation of Hh-mediated Hh oligomers is thought to be an important feature of normal Hh signaling, but no conserved self-interaction between Hh proteins is apparent from inspection of 14 independent Hh-containing crystal lattices.Hedgehog (Hh) 2 signaling proteins mediate key cell differentiation and tissue patterning events during animal development (1-3). Hh proteins generate tissue pattern, and fit the classical definition of a morphogen, by forming concentration gradients emanating from sites of secretion and eliciting different cell fate responses at different concentrations (3, 4). Three Hh homologs are present in mammals: Sonic Hh (Shh), Indian Hh (Ihh), and Desert Hh (Dhh), but only a single Hh protein is present in Drosophila. Shh is essential for normal development of the nervous system, skeleton, and limbs (3). Ihh and Dhh are required for normal skeletal and testis development, respectively (5, 6). Hh proteins also play a role in maintenance and regeneration of adult tissues and stem cells (7,8), and abnormal Hh signaling has been implicated in several cancers (9). Drugs targeting the Hh pathway are currently in late stage clinical trials for the treatment of basal cell carcinoma (10) and early stage trials for treatment of breast, pancreatic, ovarian, brain, and gastric cancers (10, 11).Hh distribution and responsiveness are tightly regulated, and many factors influence the secretion, movement, and reception of Hh signals (12, 13). Hh proteins are synthesized as 45-kDa precursors that cleave themselves to generate an N-terminal 19-kDa fragment (HhN) and a C-terminal 25-kDa fragment (HhC). HhC mediates this reaction, which also results in the covalent attachment of cholesterol to the C terminus of HhN (14). HhN is palmitoylated at its N terminus in a separate reaction, and dually lipidated HhN is secreted as part of a multivalent lipoprotein particle (13,15). HhN mediates all known Hh signaling activities, and HhN lipidation and multivalency are required both for full potency and to regulate the distribution of HhN (12). Reception of the Hh signal involves Patched (Ptc) (16), a 12-pass integral membrane protein with homology to proton-driven bacterial transporters, and Smoothened (17), a 7-pass integral membrane protein with homology to G-protein coupled receptors. In the absence of Hh, Ptc inhibits the activity of Smoothened (17). Hh relieves this inhibition, resulting in the activation of Smoothened and downstream effectors that converge on Gli family transcription factors to alter expression levels of target genes (17).Despite high sequence similarity between Hh proteins, not all interactions between Hh proteins and cell-surface receptors are conserved between vertebrates and invertebrates. Vertebrate Hh proteins appear to interact directly with cognate Ptc proteins, but a direct interaction between the N-terminal signaling domai...

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Hedgehog lipids: Promotors of alternative morphogen release and signaling?

et al. 2021

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Two posttranslational lipid modifications present on all Hedgehog (Hh) morphogensan N-terminal palmitate and a C-terminal cholesterol-are established and essential regulators of Hh biofunction. Yet, for several decades, the question of exactly how both lipids contribute to Hh signaling remained obscure. Recently, cryogenic electron microscopy revealed different modes by which one or both lipids may contribute directly to Hh binding and signaling to its receptor Patched1 (Ptc). Some of these modes demand that the established release factor Dispatched1 (Disp) extracts dual-lipidated Hh from the cell surface, and that another known upstream signaling modulator called Scube2 chaperones the dual-lipidated morphogen to Ptc. By mechanistically and biochemically aligning this concept with established in vivo and recent in vitro findings, this reflection identifies remaining questions in lipidated Hh transport and evaluates additional mechanisms of Disp-and Scube2-regulated release of a second bioactive Hh fraction that has one or both lipids removed.

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Nanoscale Organization of Hedgehog Is Essential for Long-Range Signaling

Cited by 139 publications

References 39 publications

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

All Mammalian Hedgehog Proteins Interact with Cell Adhesion Molecule, Down-regulated by Oncogenes (CDO) and Brother of CDO (BOC) in a Conserved Manner

Hedgehog lipids: Promotors of alternative morphogen release and signaling?

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