6bdz

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ADAM10 Extracellular Domain Bound by the 11G2 Fab

Structural highlights

6bdz is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.1Å
Ligands:CA, MAN, NAG, SO4, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ADA10_HUMAN Reticulate acropigmentation of Kitamura. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry.

Function

ADA10_HUMAN Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146).[UniProtKB:O35598][1] [2] [3] [4] [5] [6] [7] [8] [9]

Publication Abstract from PubMed

Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic alpha-secretase cleavage of the Alzheimer's precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.

Structural Basis for Regulated Proteolysis by the alpha-Secretase ADAM10.,Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, Janes PW, Rubinstein E, Nikolov DB, Skiniotis G, Kruse AC, Blacklow SC Cell. 2017 Dec 14;171(7):1638-1648.e7. doi: 10.1016/j.cell.2017.11.014. Epub 2017, Dec 7. PMID:29224781[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Vincent B, Paitel E, Saftig P, Frobert Y, Hartmann D, De Strooper B, Grassi J, Lopez-Perez E, Checler F. The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein. J Biol Chem. 2001 Oct 12;276(41):37743-6. doi: 10.1074/jbc.M105677200. Epub 2001 , Jul 26. PMID:11477090 doi:http://dx.doi.org/10.1074/jbc.M105677200
  2. ↑ Lemjabbar H, Basbaum C. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nat Med. 2002 Jan;8(1):41-6. doi: 10.1038/nm0102-41. PMID:11786905 doi:http://dx.doi.org/10.1038/nm0102-41
  3. ↑ Gutwein P, Mechtersheimer S, Riedle S, Stoeck A, Gast D, Joumaa S, Zentgraf H, Fogel M, Altevogt DP. ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles. FASEB J. 2003 Feb;17(2):292-4. doi: 10.1096/fj.02-0430fje. Epub 2002 Dec 3. PMID:12475894 doi:http://dx.doi.org/10.1096/fj.02-0430fje
  4. ↑ Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB. Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell. 2005 Oct 21;123(2):291-304. PMID:16239146 doi:10.1016/j.cell.2005.08.014
  5. ↑ Kirkin V, Cahuzac N, Guardiola-Serrano F, Huault S, Luckerath K, Friedmann E, Novac N, Wels WS, Martoglio B, Hueber AO, Zornig M. The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells. Cell Death Differ. 2007 Sep;14(9):1678-87. Epub 2007 Jun 8. PMID:17557115 doi:http://dx.doi.org/10.1038/sj.cdd.4402175
  6. ↑ Martin L, Fluhrer R, Haass C. Substrate requirements for SPPL2b-dependent regulated intramembrane proteolysis. J Biol Chem. 2009 Feb 27;284(9):5662-70. doi: 10.1074/jbc.M807485200. Epub 2008, Dec 29. PMID:19114711 doi:http://dx.doi.org/10.1074/jbc.M807485200
  7. ↑ Rabquer BJ, Amin MA, Teegala N, Shaheen MK, Tsou PS, Ruth JH, Lesch CA, Imhof BA, Koch AE. Junctional adhesion molecule-C is a soluble mediator of angiogenesis. J Immunol. 2010 Aug 1;185(3):1777-85. doi: 10.4049/jimmunol.1000556. Epub 2010, Jun 30. PMID:20592283 doi:10.4049/jimmunol.1000556
  8. ↑ Jiang J, Wu S, Wang W, Chen S, Peng J, Zhang X, Wu Q. Ectodomain shedding and autocleavage of the cardiac membrane protease corin. J Biol Chem. 2011 Mar 25;286(12):10066-72. doi: 10.1074/jbc.M110.185082. Epub, 2011 Feb 2. PMID:21288900 doi:http://dx.doi.org/10.1074/jbc.M110.185082
  9. ↑ Jouannet S, Saint-Pol J, Fernandez L, Nguyen V, Charrin S, Boucheix C, Brou C, Milhiet PE, Rubinstein E. TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization. Cell Mol Life Sci. 2016 May;73(9):1895-915. doi: 10.1007/s00018-015-2111-z. Epub , 2015 Dec 19. PMID:26686862 doi:http://dx.doi.org/10.1007/s00018-015-2111-z
  10. ↑ Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, Janes PW, Rubinstein E, Nikolov DB, Skiniotis G, Kruse AC, Blacklow SC. Structural Basis for Regulated Proteolysis by the alpha-Secretase ADAM10. Cell. 2017 Dec 14;171(7):1638-1648.e7. doi: 10.1016/j.cell.2017.11.014. Epub 2017, Dec 7. PMID:29224781 doi:http://dx.doi.org/10.1016/j.cell.2017.11.014

Contents


PDB ID 6bdz

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