Sonic Hedgehog: Difference between revisions

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= Function =

The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues thought to assist hydrolysis, are highly conserved among vertebrate Hh proteins. A potential hydrolytic activity is therefore expected to play an important cellular role. In pursuit of a substrate for Shh-N, it was found that <scene name='Sandbox_191/Scene3/6'>Ala 194 and Lys 195</scene> near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second Shh-N molecule. This indicates that the protein may be capable of cleaving between Lys 195 and Ser 196 within its own C-terminus <ref name="Palm"/>. This is the most highly conserved region of Hh proteins<ref>PMID: 8807822</ref>. The suspected hydrolytic function of Shh-N has been suggested to liberate the tethered protein from the cell membrane to facilitate long-range signaling <ref name="Palm"/>. However, other possible substrates for Shh-N proteolysis are also likely, including an Shh receptor or other signaling ~~proteins~~ involved in the Shh pathway.

The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues thought to assist hydrolysis, are highly conserved among vertebrate Hh proteins. A potential hydrolytic activity is therefore expected to play an important cellular role. In pursuit of a substrate for Shh-N, it was found that <scene name='Sandbox_191/Scene3/6'>Ala 194 and Lys 195</scene> near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second Shh-N molecule. This indicates that the protein may be capable of cleaving between Lys 195 and Ser 196 within its own C-terminus <ref name="Palm"/>. This is the most highly conserved region of Hh proteins<ref>PMID: 8807822</ref>. The suspected hydrolytic function of Shh-N has been suggested to liberate the tethered protein from the cell membrane to facilitate long-range signaling <ref name="Palm"/>. However, other possible substrates for Shh-N proteolysis are also likely, including an Shh receptor or other kinds of signaling molecules involved in the Shh pathway.

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

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[[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"/>.

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 (Figure 2). 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 (Figure 2) <ref name="ShhGli"/>.

~~== Mutations ==~~

='''References'''=

Sonic Hedgehog: Difference between revisions

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@@ Line 18: / Line 18: @@
 = Function =
-The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues thought to assist hydrolysis, are highly conserved among vertebrate Hh proteins. A potential hydrolytic activity is therefore expected to play an important cellular role. In pursuit of a substrate for Shh-N, it was found that <scene name='Sandbox_191/Scene3/6'>Ala 194 and Lys 195</scene> near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second Shh-N molecule. This indicates that the protein may be capable of cleaving between Lys 195 and Ser 196 within its own C-terminus <ref name="Palm"/>. This is the most highly conserved region of Hh proteins<ref>PMID: 8807822</ref>. The suspected hydrolytic function of Shh-N has been suggested to liberate the tethered protein from the cell membrane to facilitate long-range signaling <ref name="Palm"/>. However, other possible substrates for Shh-N proteolysis are also likely, including an Shh receptor or other signaling proteins involved in the Shh pathway.
+The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues thought to assist hydrolysis, are highly conserved among vertebrate Hh proteins. A potential hydrolytic activity is therefore expected to play an important cellular role. In pursuit of a substrate for Shh-N, it was found that <scene name='Sandbox_191/Scene3/6'>Ala 194 and Lys 195</scene> near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second Shh-N molecule. This indicates that the protein may be capable of cleaving between Lys 195 and Ser 196 within its own C-terminus <ref name="Palm"/>. This is the most highly conserved region of Hh proteins<ref>PMID: 8807822</ref>. The suspected hydrolytic function of Shh-N has been suggested to liberate the tethered protein from the cell membrane to facilitate long-range signaling <ref name="Palm"/>. However, other possible substrates for Shh-N proteolysis are also likely, including an Shh receptor or other kinds of signaling molecules involved in the Shh pathway.
 == Sonic Signaling: The Shh-Gli Pathway ==
@@ Line 24: / Line 24: @@
 [[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"/>.
+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 (Figure 2). 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 (Figure 2) <ref name="ShhGli"/>.
-== Mutations ==
 ='''References'''=
 <references/>