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| | ==Crystal structure of mouse fetuin-B== | | ==Crystal structure of mouse fetuin-B== |
| - | <StructureSection load='6hpv' size='340' side='right' caption='[[6hpv]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='6hpv' size='340' side='right'caption='[[6hpv]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6hpv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HPV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HPV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6hpv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HPV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HPV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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]] 2.3Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6hpv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hpv OCA], [http://pdbe.org/6hpv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hpv RCSB], [http://www.ebi.ac.uk/pdbsum/6hpv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hpv ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=6hpv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hpv OCA], [https://pdbe.org/6hpv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hpv RCSB], [https://www.ebi.ac.uk/pdbsum/6hpv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hpv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FETUB_MOUSE FETUB_MOUSE]] Protease inhibitor required for egg fertilization. Required to prevent premature zona pellucida hardening before fertilization, probably by inhibiting the protease activity of ASTL, a protease that mediates the cleavage of ZP2 and triggers zona pellucida hardening.<ref>PMID:23562279</ref> | + | [https://www.uniprot.org/uniprot/FETUB_MOUSE FETUB_MOUSE] Protease inhibitor required for egg fertilization. Required to prevent premature zona pellucida hardening before fertilization, probably by inhibiting the protease activity of ASTL, a protease that mediates the cleavage of ZP2 and triggers zona pellucida hardening.<ref>PMID:23562279</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | A set of orthologous plasma proteins found in human, sheep, pig, cow and rodents, now collectively designated fetuin-A, constitutes the fetuin family. Fetuin-A has been identified as a major protein during fetal life and is also involved in important functions such as inhibition of the insulin receptor tyrosine kinase activity, protease inhibitory activities and development-associated regulation of calcium metabolism and osteogenesis. Furthermore, fetuin-A is a key partner in the recovery phase of an acute inflammatory response. We now describe a second protein of the fetuin family, called fetuin-B, which is found at least in human and rodents. On grounds of domain homology, overall conservation of cysteine residues and chromosomal assignments of the corresponding genes in these species, fetuin-B is unambiguously a paralogue of fetuin-A. Yet, fetuin-A and fetuin-B exhibit significant differences at the amino acid sequence level, notably including variations with respect to the archetypal fetuin-specific signature. Differences and similarities in terms of gene regulation were also observed. Indeed, studies performed during development in rat and mouse showed for the first time high expression of a member of the fetuin family in adulthood, as shown with the fetuin-B mRNA in rat. However, like its fetuin-A counterpart, the fetuin-B mRNA level is down-regulated during the acute phase of experimentally induced inflammation in rat. | + | Mammalian fetuin-A and fetuin-B are abundant serum proteins with pleiotropic functions. Fetuin-B is a highly selective and potent inhibitor of metallo-peptidases (MPs) of the astacin family, which includes ovastacin in mammals. By inhibiting ovastacin, fetuin-B is essential for female fertility. The crystal structure of fetuin-B was determined unbound and in complex with archetypal astacin, and it was found that the inhibitor has tandem cystatin-type modules (CY1 and CY2). They are connected by an exposed linker with a rigid, disulfide-linked 'CPDCP-trunk', and are followed by a C-terminal region (CTR) with little regular secondary structure. The CPDCP-trunk and a hairpin of CY2 form a bipartite wedge, which slots into the active-site cleft of the MP. These elements occupy the nonprimed and primed sides of the cleft, respectively, but spare the specificity pocket so that the inhibitor is not cleaved. The aspartate in the trunk blocks the catalytic zinc of astacin, while the CY2 hairpin binds through a QWVXGP motif. The CY1 module assists in structural integrity and the CTR is not involved in inhibition, as verified by in vitro studies using a cohort of mutants and variants. Overall, the inhibition conforms to a novel 'raised-elephant-trunk' mechanism for MPs, which is reminiscent of single-domain cystatins that target cysteine peptidases. Over 200 sequences from vertebrates have been annotated as fetuin-B, underpinning its ubiquity and physiological relevance; accordingly, sequences with conserved CPDCP- and QWVXGP-derived motifs have been found from mammals to cartilaginous fishes. Thus, the raised-elephant-trunk mechanism is likely to be generally valid for the inhibition of astacins by orthologs of fetuin-B. |
| | | | |
| - | Fetuin-B, a second member of the fetuin family in mammals.,Olivier E, Soury E, Ruminy P, Husson A, Parmentier F, Daveau M, Salier JP Biochem J. 2000 Sep 1;350 Pt 2:589-97. PMID:10947975<ref>PMID:10947975</ref>
| + | Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition.,Cuppari A, Korschgen H, Fahrenkamp D, Schmitz C, Guevara T, Karmilin K, Kuske M, Olf M, Dietzel E, Yiallouros I, de Sanctis D, Goulas T, Weiskirchen R, Jahnen-Dechent W, Floehr J, Stoecker W, Jovine L, Gomis-Ruth FX IUCrJ. 2019 Feb 28;6(Pt 2):317-330. doi: 10.1107/S2052252519001568. eCollection, 2019 Mar 1. PMID:30867929<ref>PMID:30867929</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dietzel, E]] | + | [[Category: Large Structures]] |
| - | [[Category: Fahrenkamp, D]] | + | [[Category: Mus musculus]] |
| - | [[Category: Jovine, L]] | + | [[Category: Dietzel E]] |
| - | [[Category: Sanctis, D de]] | + | [[Category: Fahrenkamp D]] |
| - | [[Category: Cystatin domain]] | + | [[Category: Jovine L]] |
| - | [[Category: Egg coat]] | + | [[Category: De Sanctis D]] |
| - | [[Category: Fertilization]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Hardening]]
| + | |
| - | [[Category: Hydrolase inhibitor]]
| + | |
| - | [[Category: Liver-secreted protein]]
| + | |
| - | [[Category: Metalloprotease inhibitor]]
| + | |
| - | [[Category: Ovastacin]]
| + | |
| - | [[Category: Zona pellucida]]
| + | |
| - | [[Category: Zp2]]
| + | |
| Structural highlights
Function
FETUB_MOUSE Protease inhibitor required for egg fertilization. Required to prevent premature zona pellucida hardening before fertilization, probably by inhibiting the protease activity of ASTL, a protease that mediates the cleavage of ZP2 and triggers zona pellucida hardening.[1]
Publication Abstract from PubMed
Mammalian fetuin-A and fetuin-B are abundant serum proteins with pleiotropic functions. Fetuin-B is a highly selective and potent inhibitor of metallo-peptidases (MPs) of the astacin family, which includes ovastacin in mammals. By inhibiting ovastacin, fetuin-B is essential for female fertility. The crystal structure of fetuin-B was determined unbound and in complex with archetypal astacin, and it was found that the inhibitor has tandem cystatin-type modules (CY1 and CY2). They are connected by an exposed linker with a rigid, disulfide-linked 'CPDCP-trunk', and are followed by a C-terminal region (CTR) with little regular secondary structure. The CPDCP-trunk and a hairpin of CY2 form a bipartite wedge, which slots into the active-site cleft of the MP. These elements occupy the nonprimed and primed sides of the cleft, respectively, but spare the specificity pocket so that the inhibitor is not cleaved. The aspartate in the trunk blocks the catalytic zinc of astacin, while the CY2 hairpin binds through a QWVXGP motif. The CY1 module assists in structural integrity and the CTR is not involved in inhibition, as verified by in vitro studies using a cohort of mutants and variants. Overall, the inhibition conforms to a novel 'raised-elephant-trunk' mechanism for MPs, which is reminiscent of single-domain cystatins that target cysteine peptidases. Over 200 sequences from vertebrates have been annotated as fetuin-B, underpinning its ubiquity and physiological relevance; accordingly, sequences with conserved CPDCP- and QWVXGP-derived motifs have been found from mammals to cartilaginous fishes. Thus, the raised-elephant-trunk mechanism is likely to be generally valid for the inhibition of astacins by orthologs of fetuin-B.
Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition.,Cuppari A, Korschgen H, Fahrenkamp D, Schmitz C, Guevara T, Karmilin K, Kuske M, Olf M, Dietzel E, Yiallouros I, de Sanctis D, Goulas T, Weiskirchen R, Jahnen-Dechent W, Floehr J, Stoecker W, Jovine L, Gomis-Ruth FX IUCrJ. 2019 Feb 28;6(Pt 2):317-330. doi: 10.1107/S2052252519001568. eCollection, 2019 Mar 1. PMID:30867929[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dietzel E, Wessling J, Floehr J, Schafer C, Ensslen S, Denecke B, Rosing B, Neulen J, Veitinger T, Spehr M, Tropartz T, Tolba R, Renne T, Egert A, Schorle H, Gottenbusch Y, Hildebrand A, Yiallouros I, Stocker W, Weiskirchen R, Jahnen-Dechent W. Fetuin-B, a liver-derived plasma protein is essential for fertilization. Dev Cell. 2013 Apr 15;25(1):106-12. doi: 10.1016/j.devcel.2013.03.001. Epub 2013 , Apr 4. PMID:23562279 doi:http://dx.doi.org/10.1016/j.devcel.2013.03.001
- ↑ Cuppari A, Korschgen H, Fahrenkamp D, Schmitz C, Guevara T, Karmilin K, Kuske M, Olf M, Dietzel E, Yiallouros I, de Sanctis D, Goulas T, Weiskirchen R, Jahnen-Dechent W, Floehr J, Stoecker W, Jovine L, Gomis-Ruth FX. Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition. IUCrJ. 2019 Feb 28;6(Pt 2):317-330. doi: 10.1107/S2052252519001568. eCollection, 2019 Mar 1. PMID:30867929 doi:http://dx.doi.org/10.1107/S2052252519001568
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