Sonic Hedgehog: Difference between revisions

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= Introduction =

Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins, which serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues<ref>PMID: 7867057</ref>. First discovered in ''Drosophila'', where mutations of the single ''Hedgehog'' gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - ''Sonic'', ''Desert'', and ''Indian hedgehog''<ref>PMID: 7916661</ref>. With the ability to control such fundamental processes as the anterioposterior patterning of vertebrate limb buds<ref>PMID: 8269518</ref>, the formation of motor neurons in the neural tube <ref>PMID: 7736596</ref>, and the development and maintenance of tissues and organs<ref>PMID: 10980429</ref>, Shh is the most well-studied member of the Hh signaling proteins<ref>PMID: 10753901</ref>. Excessive signaling in adult cells has been implicated in the development of several human cancers<ref>PMID: 14737121</ref><ref name="Path">PMID: 12044012</ref>.

Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins, which serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues<ref>PMID: 7867057</ref>. First discovered in ''Drosophila'', where mutations of the single ''Hedgehog'' gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - ''Sonic'', ''Desert'', and ''Indian hedgehog''<ref>PMID: 7916661</ref>. With the ability to control such fundamental processes as the anterioposterior patterning of vertebrate limb buds<ref>PMID: 8269518</ref>, the formation of motor neurons in the neural tube <ref>PMID: 7736596</ref>, and the development and maintenance of tissues and organs<ref>PMID: 10980429</ref>, Shh is the most well-studied member of the Hh signaling proteins<ref name="papinsky">PMID: 10753901</ref>. Excessive signaling in adult cells has been implicated in the development of several human cancers<ref>PMID: 14737121</ref><ref name="Path">PMID: 12044012</ref>.

= Biosynthesis =

As with all members of the Hh family, Shh biosynthesis begins with an unusual molecular processing event. Following cleavage of its signal peptide, the Shh precursor protein is autocatalytically cleaved into two functionally distinct domains, a 19-kDa amino-terminal domain (Shh-N) and a 27-kDa carboxy-terminal domain (Shh-C)<ref>PMID: 7891723</ref>. Spanning residues 24 to 197 in human Shh, Shh-N is responsible for all of the local and long-range signaling activities of Shh. Shh-C possesses an intramolecular transferase activity responsible for covalent attachment of a molecule of cholesterol to the C-terminus of Shh-N. The addition of cholesterol serves to tether Shh-N to the cell membrane, restricting its range of activity to that of local signaling only<ref>PMID: 8824192</ref>. A second modification involving the attachment of a palmitoyl group to Cys-24 on the protein's N-terminus has recently been discovered in insect and mammalian cells. This N-terminal modification is thought to increase the potency of the Shh-N signal as much as 30-fold<ref>PMID: 9593755</ref>.

As with all members of the Hh family, Shh biosynthesis begins with an unusual molecular processing event. Following cleavage of its signal peptide, the Shh precursor protein is autocatalytically cleaved into two functionally distinct domains, a 19-kDa amino-terminal domain (Shh-N) and a 27-kDa carboxy-terminal domain (Shh-C)<ref>PMID: 7891723</ref>. Spanning residues 24 to 197 in human Shh, Shh-N is responsible for all of the local and long-range signaling activities of Shh. Shh-C possesses an intramolecular transferase activity responsible for covalent attachment of a molecule of cholesterol to the C-terminus of Shh-N <ref name="papinsky"/>. The addition of cholesterol serves to tether Shh-N to the cell membrane, restricting its range of activity to that of local signaling only<ref>PMID: 8824192</ref>. A second modification involving the attachment of a palmitoyl group to Cys-24 on the protein's N-terminus has recently been discovered in insect and mammalian cells. This N-terminal modification is thought to increase the potency of the Shh-N signal as much as 30-fold<ref>PMID: 9593755</ref>.

= Structural Overview =

Sonic Hedgehog: Difference between revisions

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 = Introduction =
-Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins, which serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues<ref>PMID: 7867057</ref>. First discovered in ''Drosophila'', where mutations of the single ''Hedgehog'' gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - ''Sonic'', ''Desert'', and ''Indian hedgehog''<ref>PMID: 7916661</ref>. With the ability to control such fundamental processes as the anterioposterior patterning of vertebrate limb buds<ref>PMID: 8269518</ref>, the formation of motor neurons in the neural tube <ref>PMID: 7736596</ref>, and the development and maintenance of tissues and organs<ref>PMID: 10980429</ref>, Shh is the most well-studied member of the Hh signaling proteins<ref>PMID: 10753901</ref>. Excessive signaling in adult cells has been implicated in the development of several human cancers<ref>PMID: 14737121</ref><ref name="Path">PMID: 12044012</ref>.
+Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins, which serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues<ref>PMID: 7867057</ref>. First discovered in ''Drosophila'', where mutations of the single ''Hedgehog'' gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - ''Sonic'', ''Desert'', and ''Indian hedgehog''<ref>PMID: 7916661</ref>. With the ability to control such fundamental processes as the anterioposterior patterning of vertebrate limb buds<ref>PMID: 8269518</ref>, the formation of motor neurons in the neural tube <ref>PMID: 7736596</ref>, and the development and maintenance of tissues and organs<ref>PMID: 10980429</ref>, Shh is the most well-studied member of the Hh signaling proteins<ref name="papinsky">PMID: 10753901</ref>. Excessive signaling in adult cells has been implicated in the development of several human cancers<ref>PMID: 14737121</ref><ref name="Path">PMID: 12044012</ref>.
 = Biosynthesis =
-As with all members of the Hh family, Shh biosynthesis begins with an unusual molecular processing event. Following cleavage of its signal peptide, the Shh precursor protein is autocatalytically cleaved into two functionally distinct domains, a 19-kDa amino-terminal domain (Shh-N) and a 27-kDa carboxy-terminal domain (Shh-C)<ref>PMID: 7891723</ref>. Spanning residues 24 to 197 in human Shh, Shh-N is responsible for all of the local and long-range signaling activities of Shh. Shh-C possesses an intramolecular transferase activity responsible for covalent attachment of a molecule of cholesterol to the C-terminus of Shh-N. The addition of cholesterol serves to tether Shh-N to the cell membrane, restricting its range of activity to that of local signaling only<ref>PMID: 8824192</ref>. A second modification involving the attachment of a palmitoyl group to Cys-24 on the protein's N-terminus has recently been discovered in insect and mammalian cells. This N-terminal modification is thought to increase the potency of the Shh-N signal as much as 30-fold<ref>PMID: 9593755</ref>.
+As with all members of the Hh family, Shh biosynthesis begins with an unusual molecular processing event. Following cleavage of its signal peptide, the Shh precursor protein is autocatalytically cleaved into two functionally distinct domains, a 19-kDa amino-terminal domain (Shh-N) and a 27-kDa carboxy-terminal domain (Shh-C)<ref>PMID: 7891723</ref>. Spanning residues 24 to 197 in human Shh, Shh-N is responsible for all of the local and long-range signaling activities of Shh. Shh-C possesses an intramolecular transferase activity responsible for covalent attachment of a molecule of cholesterol to the C-terminus of Shh-N <ref name="papinsky"/>. The addition of cholesterol serves to tether Shh-N to the cell membrane, restricting its range of activity to that of local signaling only<ref>PMID: 8824192</ref>. A second modification involving the attachment of a palmitoyl group to Cys-24 on the protein's N-terminus has recently been discovered in insect and mammalian cells. This N-terminal modification is thought to increase the potency of the Shh-N signal as much as 30-fold<ref>PMID: 9593755</ref>.
 = Structural Overview =