|
|
| Line 3: |
Line 3: |
| | <StructureSection load='3gax' size='340' side='right'caption='[[3gax]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='3gax' size='340' side='right'caption='[[3gax]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3gax]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GAX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GAX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3gax]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GAX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GAX FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1g96|1g96]], [[1r4c|1r4c]], [[1tij|1tij]]</div></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CST3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3gax FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gax OCA], [https://pdbe.org/3gax PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gax RCSB], [https://www.ebi.ac.uk/pdbsum/3gax PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gax ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3gax FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gax OCA], [https://pdbe.org/3gax PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gax RCSB], [https://www.ebi.ac.uk/pdbsum/3gax PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gax ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/CYTC_HUMAN CYTC_HUMAN]] Defects in CST3 are the cause of amyloidosis type 6 (AMYL6) [MIM:[https://omim.org/entry/105150 105150]]; also known as hereditary cerebral hemorrhage with amyloidosis (HCHWA), cerebral amyloid angiopathy (CAA) or cerebroarterial amyloidosis Icelandic type. AMYL6 is a hereditary generalized amyloidosis due to cystatin C amyloid deposition. Cystatin C amyloid accumulates in the walls of arteries, arterioles, and sometimes capillaries and veins of the brain, and in various organs including lymphoid tissue, spleen, salivary glands, and seminal vesicles. Amyloid deposition in the cerebral vessels results in cerebral amyloid angiopathy, cerebral hemorrhage and premature stroke. Cystatin C levels in the cerebrospinal fluid are abnormally low.<ref>PMID:2541223</ref> <ref>PMID:1352269</ref> Genetic variations in CST3 are associated with age-related macular degeneration type 11 (ARMD11) [MIM:[https://omim.org/entry/611953 611953]]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.<ref>PMID:11815350</ref>
| + | [https://www.uniprot.org/uniprot/CYTC_HUMAN CYTC_HUMAN] Defects in CST3 are the cause of amyloidosis type 6 (AMYL6) [MIM:[https://omim.org/entry/105150 105150]; also known as hereditary cerebral hemorrhage with amyloidosis (HCHWA), cerebral amyloid angiopathy (CAA) or cerebroarterial amyloidosis Icelandic type. AMYL6 is a hereditary generalized amyloidosis due to cystatin C amyloid deposition. Cystatin C amyloid accumulates in the walls of arteries, arterioles, and sometimes capillaries and veins of the brain, and in various organs including lymphoid tissue, spleen, salivary glands, and seminal vesicles. Amyloid deposition in the cerebral vessels results in cerebral amyloid angiopathy, cerebral hemorrhage and premature stroke. Cystatin C levels in the cerebrospinal fluid are abnormally low.<ref>PMID:2541223</ref> <ref>PMID:1352269</ref> Genetic variations in CST3 are associated with age-related macular degeneration type 11 (ARMD11) [MIM:[https://omim.org/entry/611953 611953]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.<ref>PMID:11815350</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/CYTC_HUMAN CYTC_HUMAN]] As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.
| + | [https://www.uniprot.org/uniprot/CYTC_HUMAN CYTC_HUMAN] As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 35: |
Line 34: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Grubb, A]] | + | [[Category: Grubb A]] |
| - | [[Category: Hernandez-Santoyo, A]] | + | [[Category: Hernandez-Santoyo A]] |
| - | [[Category: Jaskolski, M]] | + | [[Category: Jaskolski M]] |
| - | [[Category: Kolodziejczyk, R]] | + | [[Category: Kolodziejczyk R]] |
| - | [[Category: Michalska, K]] | + | [[Category: Michalska K]] |
| - | [[Category: Wahlbom, M]] | + | [[Category: Wahlbom M]] |
| - | [[Category: 3d domain swapping]]
| + | |
| - | [[Category: Amyloid]]
| + | |
| - | [[Category: Amyloidosis]]
| + | |
| - | [[Category: Cysteine protease inhibitor]]
| + | |
| - | [[Category: Disease mutation]]
| + | |
| - | [[Category: Hereditary cystatin c amyloid angiopathy]]
| + | |
| - | [[Category: Hydrolase inhibitor]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Protease inhibitor]]
| + | |
| - | [[Category: Protein aggregation]]
| + | |
| - | [[Category: Protein engineering]]
| + | |
| - | [[Category: Secreted]]
| + | |
| - | [[Category: Thiol protease inhibitor]]
| + | |
| - | [[Category: Twinning]]
| + | |
| Structural highlights
Disease
CYTC_HUMAN Defects in CST3 are the cause of amyloidosis type 6 (AMYL6) [MIM:105150; also known as hereditary cerebral hemorrhage with amyloidosis (HCHWA), cerebral amyloid angiopathy (CAA) or cerebroarterial amyloidosis Icelandic type. AMYL6 is a hereditary generalized amyloidosis due to cystatin C amyloid deposition. Cystatin C amyloid accumulates in the walls of arteries, arterioles, and sometimes capillaries and veins of the brain, and in various organs including lymphoid tissue, spleen, salivary glands, and seminal vesicles. Amyloid deposition in the cerebral vessels results in cerebral amyloid angiopathy, cerebral hemorrhage and premature stroke. Cystatin C levels in the cerebrospinal fluid are abnormally low.[1] [2] Genetic variations in CST3 are associated with age-related macular degeneration type 11 (ARMD11) [MIM:611953. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.[3]
Function
CYTC_HUMAN As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human cystatin C (HCC) is a family 2 cystatin inhibitor of papain-like (C1) and legumain-related (C13) cysteine proteases. In pathophysiological processes, the nature of which is not understood, HCC is codeposited in the amyloid plaques of Alzheimer's disease or Down's syndrome. The amyloidogenic properties of HCC are greatly increased in a naturally occurring L68Q variant, resulting in fatal cerebral amyloid angiopathy in early adult life. In all crystal structures of cystatin C studied to date, the protein has been found to form 3D domain-swapped dimers, created through a conformational change of a beta-hairpin loop, L1, from the papain-binding epitope. We have created monomer-stabilized human cystatin C, with an engineered disulfide bond (L47C)-(G69C) between the structural elements that become separated upon domain swapping. The mutant has drastically reduced dimerization and fibril formation properties, but its inhibition of papain is unaltered. The structure confirms the success of the protein engineering experiment to abolish 3D domain swapping and, in consequence, amyloid fibril formation. It illustrates for the first time the fold of monomeric cystatin C and allows verification of earlier predictions based on the domain-swapped forms and on the structure of chicken cystatin. Importantly, the structure defines the so-far unknown conformation of loop L1, which is essential for the inhibition of papain-like cysteine proteases.
Crystal structure of human cystatin C stabilized against amyloid formation.,Kolodziejczyk R, Michalska K, Hernandez-Santoyo A, Wahlbom M, Grubb A, Jaskolski M FEBS J. 2010 Apr;277(7):1726-37. Epub 2010 Feb 19. PMID:20175878[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Levy E, Lopez-Otin C, Ghiso J, Geltner D, Frangione B. Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases. J Exp Med. 1989 May 1;169(5):1771-8. PMID:2541223
- ↑ Abrahamson M, Jonsdottir S, Olafsson I, Jensson O, Grubb A. Hereditary cystatin C amyloid angiopathy: identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis. Hum Genet. 1992 Jun;89(4):377-80. PMID:1352269
- ↑ Zurdel J, Finckh U, Menzer G, Nitsch RM, Richard G. CST3 genotype associated with exudative age related macular degeneration. Br J Ophthalmol. 2002 Feb;86(2):214-9. PMID:11815350
- ↑ Kolodziejczyk R, Michalska K, Hernandez-Santoyo A, Wahlbom M, Grubb A, Jaskolski M. Crystal structure of human cystatin C stabilized against amyloid formation. FEBS J. 2010 Apr;277(7):1726-37. Epub 2010 Feb 19. PMID:20175878 doi:10.1111/j.1742-4658.2010.07596.x
|
