Sandbox Reserved 1627: Difference between revisions

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====Alpha Subunits====

The alpha subunits make up the extracellular domain ([http://en.wikipedia.org/wiki/Ectodomain ectodomain]) of the insulin receptor and are the sites of insulin binding. The alpha subunit is comprised of two Leucine rich domains (L1 & L2), a Cysteine rich domain (CR), and a C-terminal alpha helix. The alpha subunits are held together by a [http://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='83/832953/Cysteine_bond/1'>cysteine residues</scene> at the CYS524 position on each alpha subunit. Two types of insulin binding sites are present in the alpha subunits, <scene name='83/832953/Sites_1_and_1_prime_location/15'>sites 1 and 1'</scene> and <scene name='83/832953/Sites_2_and_2_prime_location/12'>sites 2 and 2'</scene>. The sites are in pairs because of the heterodimeric nature of the receptor. Due to structural differences, as well as greater surface area and accessibility, binding sites 1 and 1' have much higher affinity than that of sites 2 and 2'. Insulin can also bind at sites 2 and 2', but the location on the back of the beta sheet of the FnIII-1 domain and lack of surface area decreases the likelihood of their binding site becoming occupied as quickly. <ref name="Uchikawa"> DOI 10.7554/eLife.48630 </ref> Cryo-EM has imaged insulin bound structures that displayed a T-shape conformation in the alpha subunits.<ref name="Uchikawa" />

[[Image:Harrison Image2.png|thumb|right|260px|Figure 1: Insulin receptor apo receptor. Site L1' is colored a dark green, CR' is orange, L2' is bright blue, L2 is yellow, CR is red, L1 is dark blue, FnIII-1 is brown, and FnIII-2 is light pink. Insulin is shown bound and is colored dark pink. [http://www.rcsb.org/structure/6CE7 PDB 6CE7]]]

The alpha subunits make up the extracellular domain ([http://en.wikipedia.org/wiki/Ectodomain ectodomain]) of the insulin receptor and are the sites of insulin binding. The alpha subunit is comprised of two Leucine rich domains (L1 & L2), a Cysteine rich domain (CR), and a C-terminal alpha helix. <ref name="Scapin"> PMID 29512653 </ref> The alpha subunits are held together by a [http://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='83/832953/Cysteine_bond/1'>cysteine residues</scene> at the CYS524 position on each alpha subunit. Two types of insulin binding sites are present in the alpha subunits, <scene name='83/832953/Sites_1_and_1_prime_location/15'>sites 1 and 1'</scene> and <scene name='83/832953/Sites_2_and_2_prime_location/12'>sites 2 and 2'</scene>. The sites are in pairs because of the heterodimeric nature of the receptor. Due to structural differences, as well as greater surface area and accessibility, binding sites 1 and 1' have much higher affinity than that of sites 2 and 2'. Insulin can also bind at sites 2 and 2', but the location on the back of the beta sheet of the FnIII-1 domain and lack of surface area decreases the likelihood of their binding site becoming occupied as quickly. <ref name="Uchikawa"> DOI 10.7554/eLife.48630 </ref> Cryo-EM has imaged insulin bound structures that displayed a T-shape conformation in the alpha subunits.<ref name="Uchikawa" />

[[Image:4 sites highlighted - Harrison.png|thumb|right|260px|Figure 2: The four binding sites of insulin. Sites 1 and 1' are colored green, sites 2 and 2' are colored red. [http://www.rcsb.org/structure/6SOF PDB 6SOF]]]

===Beta Subunits===

The beta subunit spans from the extracellular domain across the transmembrane region and into the intracellular portion of the insulin receptor. The beta subunit is composed of part of [http://en.wikipedia.org/wiki/Fibronectin fibronectin] domain III-2 and all of Fibronectin domain III-3. The beta subunit's FnIII-3 domain has links through the transmembrane region into the intracellular part of the membrane.[http://en.wikipedia.org/wiki/Transmission_electron_cryomicroscopy Cryo-EM] results have displayed clear representations of FnIII-2 and FnIII-3 domains, but lack in their ability to model the receptor structure throughout the transmembrane region and intracellular region. Although, the FnIII-3 domain is connected to these regions, so it has been proposed that the T-shape conformation extends all the way to the tyrosine kinase domain region. [http://www.rcsb.org/structure/1IR3 PDB 1IR3]

The beta subunit spans from the extracellular domain across the transmembrane region and into the intracellular portion of the insulin receptor. The beta subunit is composed of part of [http://en.wikipedia.org/wiki/Fibronectin fibronectin] domain III-2 and all of Fibronectin domain III-3. <ref name="Scapin" /> The beta subunit's FnIII-3 domain has links through the transmembrane region into the intracellular part of the membrane.[http://en.wikipedia.org/wiki/Transmission_electron_cryomicroscopy Cryo-EM] results have displayed clear representations of FnIII-2 and FnIII-3 domains, but lack in their ability to model the receptor structure throughout the transmembrane region and intracellular region. Although, the FnIII-3 domain is connected to these regions, so it has been proposed that the T-shape conformation extends all the way to the tyrosine kinase domain region. [http://www.rcsb.org/structure/1IR3 PDB 1IR3]

== Function==

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@@ Line 10: / Line 10: @@
 ====Alpha Subunits====
-The alpha subunits make up the extracellular domain ([http://en.wikipedia.org/wiki/Ectodomain ectodomain]) of the insulin receptor and are the sites of insulin binding. The alpha subunit is comprised of two Leucine rich domains (L1 & L2), a Cysteine rich domain (CR), and a C-terminal alpha helix. The alpha subunits are held together by a [http://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='83/832953/Cysteine_bond/1'>cysteine residues</scene> at the CYS524 position on each alpha subunit. Two types of insulin binding sites are present in the alpha subunits, <scene name='83/832953/Sites_1_and_1_prime_location/15'>sites 1 and 1'</scene> and <scene name='83/832953/Sites_2_and_2_prime_location/12'>sites 2 and 2'</scene>. The sites are in pairs because of the heterodimeric nature of the receptor. Due to structural differences, as well as greater surface area and accessibility, binding sites 1 and 1' have much higher affinity than that of sites 2 and 2'. Insulin can also bind at sites 2 and 2', but the location on the back of the beta sheet of the FnIII-1 domain and lack of surface area decreases the likelihood of their binding site becoming occupied as quickly. <ref name="Uchikawa"> DOI 10.7554/eLife.48630 </ref> Cryo-EM has imaged insulin bound structures that displayed a T-shape conformation in the alpha subunits.<ref name="Uchikawa" />
+[[Image:Harrison Image2.png|thumb|right|260px|Figure 1: Insulin receptor apo receptor. Site L1' is colored a dark green, CR' is orange, L2' is bright blue, L2 is yellow, CR is red, L1 is dark blue, FnIII-1 is brown, and FnIII-2 is light pink. Insulin is shown bound and is colored dark pink. [http://www.rcsb.org/structure/6CE7 PDB 6CE7]]]
+The alpha subunits make up the extracellular domain ([http://en.wikipedia.org/wiki/Ectodomain ectodomain]) of the insulin receptor and are the sites of insulin binding. The alpha subunit is comprised of two Leucine rich domains (L1 & L2), a Cysteine rich domain (CR), and a C-terminal alpha helix. <ref name="Scapin"> PMID 29512653 </ref> The alpha subunits are held together by a [http://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='83/832953/Cysteine_bond/1'>cysteine residues</scene> at the CYS524 position on each alpha subunit. Two types of insulin binding sites are present in the alpha subunits, <scene name='83/832953/Sites_1_and_1_prime_location/15'>sites 1 and 1'</scene> and <scene name='83/832953/Sites_2_and_2_prime_location/12'>sites 2 and 2'</scene>. The sites are in pairs because of the heterodimeric nature of the receptor. Due to structural differences, as well as greater surface area and accessibility, binding sites 1 and 1' have much higher affinity than that of sites 2 and 2'. Insulin can also bind at sites 2 and 2', but the location on the back of the beta sheet of the FnIII-1 domain and lack of surface area decreases the likelihood of their binding site becoming occupied as quickly. <ref name="Uchikawa"> DOI 10.7554/eLife.48630 </ref> Cryo-EM has imaged insulin bound structures that displayed a T-shape conformation in the alpha subunits.<ref name="Uchikawa" />
+[[Image:4 sites highlighted - Harrison.png|thumb|right|260px|Figure 2: The four binding sites of insulin. Sites 1 and 1' are colored green, sites 2 and 2' are colored red.  [http://www.rcsb.org/structure/6SOF PDB 6SOF]]]
 ===Beta Subunits===
-The beta subunit spans from the extracellular domain across the transmembrane region and into the intracellular portion of the insulin receptor. The beta subunit is composed of part of [http://en.wikipedia.org/wiki/Fibronectin fibronectin] domain III-2 and all of Fibronectin domain III-3. The beta subunit's FnIII-3 domain has links through the transmembrane region into the intracellular part of the membrane.[http://en.wikipedia.org/wiki/Transmission_electron_cryomicroscopy Cryo-EM] results have displayed clear representations of FnIII-2 and FnIII-3 domains, but lack in their ability to model the receptor structure throughout the transmembrane region and intracellular region. Although, the FnIII-3 domain is connected to these regions, so it has been proposed that the T-shape conformation extends all the way to the tyrosine kinase domain region. [http://www.rcsb.org/structure/1IR3 PDB 1IR3]
+The beta subunit spans from the extracellular domain across the transmembrane region and into the intracellular portion of the insulin receptor. The beta subunit is composed of part of [http://en.wikipedia.org/wiki/Fibronectin fibronectin] domain III-2 and all of Fibronectin domain III-3. <ref name="Scapin" /> The beta subunit's FnIII-3 domain has links through the transmembrane region into the intracellular part of the membrane.[http://en.wikipedia.org/wiki/Transmission_electron_cryomicroscopy Cryo-EM] results have displayed clear representations of FnIII-2 and FnIII-3 domains, but lack in their ability to model the receptor structure throughout the transmembrane region and intracellular region. Although, the FnIII-3 domain is connected to these regions, so it has been proposed that the T-shape conformation extends all the way to the tyrosine kinase domain region. [http://www.rcsb.org/structure/1IR3 PDB 1IR3]
 == Function==