Sonic Hedgehog: Difference between revisions

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== Structural Overview ==

The three-dimensional structure of murine Shh-N (residues 39-195) is shown as 1VHH. An α + β sandwich consisting of two <scene name='Sandbox_191/Scene2/5'> α-helices</scene> and a six-stranded, mixed <scene name='Sandbox_191/Scene3/5'> β-sheet</scene> makes up the core of the structure, along with a two-stranded, antiparallel β-sheet<ref name="Palm"/>. Although this type of folding arrangement has not yet been seen in other proteins, the presence of a <scene name='Sandbox_191/Scene4/3'>tetrahedrally coordinated zinc ion</scene> in Shh-N bears close structural resemblance to the zinc coordination sites of zinc hydrolases, including thermolysin and carboxypeptidase A. Three amino acid side chains – <scene name='Sandbox_191/Scene4/4'>His 141, Asp 148, and His 183</scene> – are bound to the zinc ion in the crystal structure, along with a single <scene name='Sandbox_191/Scene4/5'>molecule of water</scene>. Zinc ions that serve a structural role in proteins are normally coordinated by four amino acid side chains and are not usually exposed to the surrounding solvent. The presence of a zinc-bound water molecule in Shh-N, by contrast, is indicative of a catalytic function. In zinc hydrolases, the water molecule is key to the protein's enzymatic activity when its proton is removed by a nearby glutamate residue. <scene name='Sandbox_191/Scene4/6'>Glu 177</scene> (Figure 1) likely serves the same role in Shh-N, further supporting a novel, hydrolytic function for this protein. Based on the catalytic mechanisms for thermolysin and carboxypeptidase A, <scene name='Sandbox_191/Scene4/7'>His 135, His 181, and Glu 127</scene> in Shh-N are also believed to participate in a potential hydrolysis reaction<ref name="Palm">PMID: 7477329</ref>.

The three-dimensional structure of murine Shh-N (residues 39-195) is shown as 1VHH. An α + β sandwich consisting of two <scene name='Sandbox_191/Scene2/5'> α-helices</scene> and a six-stranded, mixed <scene name='Sandbox_191/Scene3/5'> β-sheet</scene> makes up the core of the structure, along with a two-stranded, antiparallel β-sheet<ref name="Palm"/>. Although this type of folding arrangement has not yet been seen in other proteins, the presence of a <scene name='Sandbox_191/Scene4/3'>tetrahedrally coordinated zinc ion</scene> in Shh-N bears close structural resemblance to the zinc coordination sites of zinc hydrolases, including thermolysin and carboxypeptidase A. Three amino acid side chains – <scene name='Sandbox_191/Scene4/4'>His 141, Asp 148, and His 183</scene> – are bound to the zinc ion in the crystal structure, along with a single <scene name='Sandbox_191/Scene4/5'>molecule of water</scene>. Zinc ions that serve a structural role in proteins are normally coordinated by four amino acid side chains and are not usually exposed to the surrounding solvent. The presence of a zinc-bound water molecule in Shh-N, by contrast, is indicative of a catalytic function. In zinc hydrolases, the water molecule is key to the protein's enzymatic activity when its proton is removed by a nearby glutamate residue. <scene name='Sandbox_191/Scene4/6'>Glu 177</scene> (Figure 1) likely serves the same role in Shh-N, further supporting a novel, hydrolytic function for this protein. Based on the catalytic mechanisms for thermolysin and carboxypeptidase A, <scene name='Sandbox_191/Scene4/7'>His 135, His 181, and Glu 127</scene> in Shh-N are also believed to participate in a potential hydrolysis reaction<ref name="Palm">PMID: 7477329</ref>. [[Image:Catalytic site.png | align='left' | size='300' | Figure 1. A close-up of the zinc coordination site of Shh-N, showing His 141, Asp 148, and His 183 separated by distances of 2.06, 1.97, and 2.08 Å. The zinc-bound water molecule is also shown in line with Glu 177, which is thought to participate in hydrolysis by abstracting a proton from the water molecule.]]

== Function ==

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== Sonic Signaling: The Shh-Gli Pathway ==

[[Image: SHH SIGNALING PATHWAY.jpg | thumb | Sonic Hedgehog signaling pathway. In the absence of Shh, Patched inhibits Smo. Inhibition of Patched by Shh activates normal developmental processes. [Note: This figure is adapted from references <ref name="Path"/> and <ref name="ShhGli">PMID: 16339192</ref>.] ]]

[[Image: SHH SIGNALING PATHWAY.jpg | thumb | Figure 2. Sonic Hedgehog signaling pathway. In the absence of Shh, Patched inhibits Smo. Inhibition of Patched by Shh activates normal developmental processes. [Note: This figure is adapted from references <ref name="Path"/> and <ref name="ShhGli">PMID: 16339192</ref>.] ]]

In the absence of a Shh signal, a transmembrane receptor protein called Patched blocks the function of Smoothened (Smo), a seven-pass transmembrane protein, by keeping it sequestered in an intracellular vesicle. When Shh binds to Patched, inhibition of Smo by Patched is relieved. Patched becomes endocytosed, and Smo translocates to the cell surface. In vertebrates, Smo localizes to the surface of the primary cilium, initiating a signaling cascade that leads to the activation of Gli transcription factors <ref name="Path"/>. Present in both the nucleus and cytoplasm, there are three of these regulatory proteins (''Gli1'', ''Gli2'', and ''Gli3''). Following Shh signaling, all three proteins can act as transcriptional activators of Shh target genes. Gli3, however, can act as both an activator and repressor; in the absence of Shh signaling, Gli3 is cleaved by the proteasome, and its truncated form accumulates in the nucleus where it represses transcription of Shh-responsive genes <ref name="ShhGli"/>.

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@@ Line 13: / Line 13: @@
 == Structural Overview ==
-The three-dimensional structure of murine Shh-N (residues 39-195) is shown as 1VHH. An α + β sandwich consisting of two <scene name='Sandbox_191/Scene2/5'> α-helices</scene> and a six-stranded, mixed <scene name='Sandbox_191/Scene3/5'> β-sheet</scene> makes up the core of the structure, along with a two-stranded, antiparallel β-sheet<ref name="Palm"/>. Although this type of folding arrangement has not yet been seen in other proteins, the presence of a <scene name='Sandbox_191/Scene4/3'>tetrahedrally coordinated zinc ion</scene> in Shh-N bears close structural resemblance to the zinc coordination sites of zinc hydrolases, including thermolysin and carboxypeptidase A. Three amino acid side chains – <scene name='Sandbox_191/Scene4/4'>His 141, Asp 148, and His 183</scene> – are bound to the zinc ion in the crystal structure, along with a single <scene name='Sandbox_191/Scene4/5'>molecule of water</scene>. Zinc ions that serve a structural role in proteins are normally coordinated by four amino acid side chains and are not usually exposed to the surrounding solvent. The presence of a zinc-bound water molecule in Shh-N, by contrast, is indicative of a catalytic function. In zinc hydrolases, the water molecule is key to the protein's enzymatic activity when its proton is removed by a nearby glutamate residue. <scene name='Sandbox_191/Scene4/6'>Glu 177</scene> (Figure 1) likely serves the same role in Shh-N, further supporting a novel, hydrolytic function for this protein. Based on the catalytic mechanisms for thermolysin and carboxypeptidase A, <scene name='Sandbox_191/Scene4/7'>His 135, His 181, and Glu 127</scene> in Shh-N are also believed to participate in a potential hydrolysis reaction<ref name="Palm">PMID: 7477329</ref>.
+The three-dimensional structure of murine Shh-N (residues 39-195) is shown as 1VHH. An α + β sandwich consisting of two <scene name='Sandbox_191/Scene2/5'> α-helices</scene> and a six-stranded, mixed <scene name='Sandbox_191/Scene3/5'> β-sheet</scene> makes up the core of the structure, along with a two-stranded, antiparallel β-sheet<ref name="Palm"/>. Although this type of folding arrangement has not yet been seen in other proteins, the presence of a <scene name='Sandbox_191/Scene4/3'>tetrahedrally coordinated zinc ion</scene> in Shh-N bears close structural resemblance to the zinc coordination sites of zinc hydrolases, including thermolysin and carboxypeptidase A. Three amino acid side chains – <scene name='Sandbox_191/Scene4/4'>His 141, Asp 148, and His 183</scene> – are bound to the zinc ion in the crystal structure, along with a single <scene name='Sandbox_191/Scene4/5'>molecule of water</scene>. Zinc ions that serve a structural role in proteins are normally coordinated by four amino acid side chains and are not usually exposed to the surrounding solvent. The presence of a zinc-bound water molecule in Shh-N, by contrast, is indicative of a catalytic function. In zinc hydrolases, the water molecule is key to the protein's enzymatic activity when its proton is removed by a nearby glutamate residue. <scene name='Sandbox_191/Scene4/6'>Glu 177</scene> (Figure 1) likely serves the same role in Shh-N, further supporting a novel, hydrolytic function for this protein. Based on the catalytic mechanisms for thermolysin and carboxypeptidase A, <scene name='Sandbox_191/Scene4/7'>His 135, His 181, and Glu 127</scene> in Shh-N are also believed to participate in a potential hydrolysis reaction<ref name="Palm">PMID: 7477329</ref>. [[Image:Catalytic site.png | align='left' | size='300' | Figure 1. A close-up of the zinc coordination site of Shh-N, showing His 141, Asp 148, and His 183 separated by distances of 2.06, 1.97, and 2.08 Å. The zinc-bound water molecule is also shown in line with Glu 177, which is thought to participate in hydrolysis by abstracting a proton from the water molecule.]]
 == Function ==
@@ Line 21: / Line 21: @@
 == Sonic Signaling: The Shh-Gli Pathway ==
-[[Image: SHH SIGNALING PATHWAY.jpg | thumb | Sonic Hedgehog signaling pathway. In the absence of Shh, Patched inhibits Smo. Inhibition of Patched by Shh activates normal developmental processes. [Note: This figure is adapted from references <ref name="Path"/> and <ref name="ShhGli">PMID: 16339192</ref>.]  ]]
+[[Image: SHH SIGNALING PATHWAY.jpg | thumb | Figure 2. Sonic Hedgehog signaling pathway. In the absence of Shh, Patched inhibits Smo. Inhibition of Patched by Shh activates normal developmental processes. [Note: This figure is adapted from references <ref name="Path"/> and <ref name="ShhGli">PMID: 16339192</ref>.]  ]]
 In the absence of a Shh signal, a transmembrane receptor protein called Patched blocks the function of Smoothened (Smo), a seven-pass transmembrane protein, by keeping it sequestered in an intracellular vesicle. When Shh binds to Patched, inhibition of Smo by Patched is relieved. Patched becomes endocytosed, and Smo translocates to the cell surface. In vertebrates, Smo localizes to the surface of the primary cilium, initiating a signaling cascade that leads to the activation of Gli transcription factors <ref name="Path"/>. Present in both the nucleus and cytoplasm, there are three of these regulatory proteins (''Gli1'', ''Gli2'', and ''Gli3''). Following Shh signaling, all three proteins can act as transcriptional activators of Shh target genes. Gli3, however, can act as both an activator and repressor; in the absence of Shh signaling, Gli3 is cleaved by the proteasome, and its truncated form accumulates in the nucleus where it represses transcription of Shh-responsive genes <ref name="ShhGli"/>.