Sandbox GGC7: Difference between revisions

Latest revision as of 22:53, 28 April 2021

Iduronate 2-sulfataseIduronate 2-sulfatase

Iduronate 2-sulfatase (IDS), also referred to as Alpha-L-iduronate sulfate sulfatase or Idursulfase, is a lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate.[1]

Function

Iduronate 2-sulfatase is located in the lysosome.[1] It is involved in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate.[1] IDS hydrolyzes the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin.[1] Dermatan sulfate and heparan sulfate are complex glycosaminoglycans, which are essentially large sugar molecules.[2] They play important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome are essential for cellular maintenance.[2] IDS is expressed in the tissues of the liver, kidney, lung, and placenta.[1]

Disease

Mutations in Iduronate 2-sulfatase on the Xq28 chromosome can lead to Mucopolysaccharidosis 2 (MPS2), more commonly known as Hunter syndrome.[1] MPS2 is an X-linked lysosomal storage disease.[1] Due to the loss of IDS activity, the disease is characterized by the intracellular accumulation of the glycosaminoglycans heparan sulfate and dermatan sulfate, which are then excreted in urine.[1] Scientists have identified over 500 mutations on the Xq28 chromosome that include rearrangements, insertions/deletions, splicing defects and nonsense point mutations.[2] It is rare to find adults with severe Hunter syndrome as the average life expectancy for those with MPS2 is 15 years of age.[1] Most children diagnosed with MPS2 have somatic abnormalities including skeletal deformities, hepatosplenomegaly, and progressive cardiopulmonary deterioration.[1] Neurological damage is also prevalent beginning with what seems to be a developmental delay and hyperactivity, but progresses to mental retardation and dementia.[1] Death from MPS2 is typically due to obstructive airway disease or cardiac failure.[1] A treatment for patients with mild Hunter syndrome is enzyme replacement therapy, which involves the recombinant human IDS.[2]

Structural highlights

ReferencesReferences

1. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Iduronate 2-sulfatase https://www.uniprot.org/uniprot/P22304#pathology_and_biotech (accessed Apr 28, 2021). 2. Demydchuk M, Hill CH, Zhou A, Bunkóczi G, Stein PE, Marchesan D, Deane JE, Read RJ. Insights into Hunter syndrome from the structure of iduronate-2-sulfatase. Nat Commun. 2017 Jun 8;8:15786. doi: 10.1038/ncomms15786. PMID: 28593992; PMCID: PMC5472762.

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-==Insulin Protease (Insulin Degrading Enzyme)==
+==Iduronate 2-sulfatase==
-<StructureSection load='3QZ2' size='340' side='right' caption='IDE Dimer' scene=''>
+<StructureSection load='5FQL' size='340' side='right' caption='Iduronate 2-sulfatase protein' scene=''>
-Insulin is a hormone that is secreted by the pancreas in response to an increased level of glucose in the blood, usually after a meal.  Insulin stimulates the muscles and adipose tissue to take up and convert it to energy or to store the excess glucose.  <scene name='75/752270/Insulin_n_to_c_terminus_rainbo/1'>Insulin</scene> is a dipeptide that contains a A and B chain.  The A chain has an N-terminal helix linked to an anti-parallel C-terminal helix.  The B chain has a central helical segment.  The two chains are connected by 3 di-sulfide bonds that join the N- and C-terminal helices of the A chain to the central helix of the B chain <ref>PMID: 16278749</ref>.  When the concentration of glucose in the blood drops, insulin is no longer needed and an insulin-degrading enzyme is produced in order to reduce the amount of insulin in the body.
+Iduronate 2-sulfatase (IDS), also referred to as Alpha-L-iduronate sulfate sulfatase or Idursulfase, is a lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate.[1]
-The insulin-degrading enzyme (IDE) is a highly conserved protease that uses <scene name='75/752270/Ide_with_insulin_b/2'>zinc (Zn2+)</scene> as a cofactor in breaking down insulin and amyloid beta-proteins <ref>doi: 10.1038/nature05143</ref>.  IDE can be found predominantly in the cytosol, however it is also located in the cell membrane, secreted into the extracellular regions and is present at the cell surfaces of neuron cells in the brain.  Insulin-degrading enzyme is also known as insulysin or insulinase and is active at neutral pH.  It can be located in red blood cells, skeletal muscle, liver and brain.
-== Structure ==
-The structure of IDE is a <scene name='75/752270/Ide_homodimer/1'>homodimer</scene> with two N-terminal domains, which forms the catalytic site and two C-terminal domains that facilitates the substrate binding <ref>DOI 10.1074/jbc.M900068200</ref>. The N-terminal domains are connected to the C-terminal domains via a 28-residue loop that forms a chamber that is shaped like a triangular prism.
-Domain 1 houses the <scene name='75/752270/Ide_monomer/1'>metal binding site</scene> with two histidine's and one glutamine(his 108, his 112 and glu 198), the <scene name='75/752270/Ide_atp_binding-active_sites/1'>active site</scene> of a glutamine (Glu 111), ATP binding site (Arg 429) and the Zn2+ ion cofactor. Several residues of domains 1 & 4 create a polar area of the triangular cavity, while residues of domains 2 & 3 create a nonpolar region of the cavity.
-There are two conformations for the enzyme, open and closed.  In the open conformation, the insulin protein enters the enzyme opening causing a conformational change that allows the enzyme to fully recognize the protein and catalyzes protein degradation.
 == Function ==
-Once the insulin molecule enters the active site and is recognized, ATP binds to the appropriate site and the enzyme changes conformation from the open state to the closed state and begins to unfold the insulin and makes two initial cleavages, one each in the middle of both the A and B chains. The enzyme then makes six more cleavages. One cleavage site right next to the first one on the A chain and 5 more on the B chain <ref>DOI 10.1074/jbc.M900068200</ref>.  Three near the middle and two near the C-terminus.  There are no cleavage sites that are near the N-terminus of either chain.
+Iduronate 2-sulfatase is located in the lysosome.[1] It is involved in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate.[1] IDS hydrolyzes the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin.[1] Dermatan sulfate and heparan sulfate are complex glycosaminoglycans, which are essentially large sugar molecules.[2] They play important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome are essential for cellular maintenance.[2] IDS is expressed in the tissues of the liver, kidney, lung, and placenta.[1]
 == Disease ==
-A mutation of Glu 111 in the active site will render the enzyme inactive or a mutation at Pro 286 will slow down the enzymatic activity.  A low functioning or inactive insulin degrading enzyme will allow the buildup of both insulin and amyloid beta-proteins.
+Mutations in Iduronate 2-sulfatase on the Xq28 chromosome can lead to Mucopolysaccharidosis 2 (MPS2), more commonly known as Hunter syndrome.[1] MPS2 is an X-linked lysosomal storage disease.[1] Due to the loss of IDS activity, the disease is characterized by the intracellular accumulation of the glycosaminoglycans heparan sulfate and dermatan sulfate, which are then excreted in urine.[1] Scientists have identified over 500 mutations on the Xq28 chromosome that include rearrangements, insertions/deletions, splicing defects and nonsense point mutations.[2] It is rare to find adults with severe Hunter syndrome as the average life expectancy for those with MPS2 is 15 years of age.[1] Most children diagnosed with MPS2 have somatic abnormalities including skeletal deformities, hepatosplenomegaly, and progressive cardiopulmonary deterioration.[1] Neurological damage is also prevalent beginning with what seems to be a developmental delay and hyperactivity, but progresses to mental retardation and dementia.[1] Death from MPS2 is typically due to obstructive airway disease or cardiac failure.[1] A treatment for patients with mild Hunter syndrome is enzyme replacement therapy, which involves the recombinant human IDS.[2]
+[[Image:Signs-and-symptoms-of-hunter-syndrome.jpg]]
-For insulin, if it is allowed to build up, insulin resistance can occur and contribute to the development of type II diabetes <ref>doi:10.1016/s0002-9440(10)63229-4</ref>. A mutation at Asp 34 will cause Hyperproinsulinemia <ref>doi:10.1210/endo.135.2.8033810</ref><ref>doi:10.1212/01.wnl.0000140292.04932.87</ref>, a disease where the body secretes insulin before it has been fully processed (proinsulin) and so does not function properly.
+== Structural highlights ==
-Several different mutations at birth or a young age can contribute to the onset of neonatal diabetes or type I diabetes.  The locations are:  Asp 24, Arg 32, Ser 32, Gly 43, Val 47, Cys 48, Cys 89, Cys 90, Tyr 96 and Cys 108.
+<scene name='75/752270/Ide_mutations/1'>Scene 1: Location of mutations</scene>
-The buildup of amyloid beta-proteins in the brain has been determined to cause the onset of Alzheimer’s disease <ref>DOI 10.1074/jbc.M900068200</ref><ref>doi:10.1038/nrd3505</ref>.  The onset of Alzheimer’s can also be contributed to the mutation of Ile 714.
+<scene name='75/752270/Ide_atp_binding-active_sites/1'>Scene 2: ATP binding active sites</scene>
+<scene name='75/752270/Ide_n_and_c_terminals/1'>Scene 3: N and C terminals</scene>
+<scene name='75/752270/Active_site_on_chain_a/1'>Scene 4: Active sites</scene>
 </StructureSection>
 == References ==
-<references/>
+. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Iduronate 2-sulfatase https://www.uniprot.org/uniprot/P22304#pathology_and_biotech (accessed Apr 28,  2021).
+. Demydchuk M, Hill CH, Zhou A, Bunkóczi G, Stein PE, Marchesan D, Deane JE, Read RJ. Insights into Hunter syndrome from the structure of iduronate-2-sulfatase. Nat Commun. 2017 Jun 8;8:15786. doi: 10.1038/ncomms15786. PMID: 28593992; PMCID: PMC5472762.