Sonic Hedgehog: Difference between revisions
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== Structural Overview == | == Structural Overview == | ||
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 native Shh-N structure, along with a two-stranded, antiparallel β-sheet. 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, including a cysteine, 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, a zinc-bound 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> is believed to serve an analogous role in Shh-N, further supporting a novel, hydrolytic function for this protein. Based on the catalytic mechanisms for thermolysin and carboxypeptidase A, other residues in Shh-N that are believed to be involved in a potential hydrolysis mechanism include <scene name='Sandbox_191/Scene4/7'>His 135, His 181, and Glu 127</scene> <ref>PMID: 7477329</ref>. | |||
<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. 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, including a cysteine, 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, a zinc-bound 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> is believed to serve an analogous role in Shh-N, further supporting a novel, hydrolytic function for this protein. Based on the catalytic mechanisms for thermolysin and carboxypeptidase A, other residues in Shh-N that are believed to be involved in a potential hydrolysis mechanism include <scene name='Sandbox_191/Scene4/7'>His 135, His 181, and Glu 127</scene> <ref>PMID: 7477329</ref>. | |||
The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues believed to assist in 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 Ala 194 and Lys 195 near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second molecule of Shh-N. This indicates that the protein may be capable of cleaving its own C-terminus, a function that has been suggested to liberate the tethered Shh-N from the cell membrane to facilitate long-range signaling. | The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues believed to assist in 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 Ala 194 and Lys 195 near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second molecule of Shh-N. This indicates that the protein may be capable of cleaving its own C-terminus, a function that has been suggested to liberate the tethered Shh-N from the cell membrane to facilitate long-range signaling. | ||
