5l0q
Crystal structure of the complex between ADAM10 D+C domain and a conformation specific mAb 8C7.
Structural highlights
FunctionADA10_BOVIN Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP). Contributes to the normal cleavage of the cellular prion protein. Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity. Controls also the proteolytic processing of Notch. Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form. Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B. May regulate the EFNA5-EPHA3 signaling (By similarity).[1] Publication Abstract from PubMedThe transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance. An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth.,Atapattu L, Saha N, Chheang C, Eissman MF, Xu K, Vail ME, Hii L, Llerena C, Liu Z, Horvay K, Abud HE, Kusebauch U, Moritz RL, Ding BS, Cao Z, Rafii S, Ernst M, Scott AM, Nikolov DB, Lackmann M, Janes PW J Exp Med. 2016 Aug 22;213(9):1741-57. doi: 10.1084/jem.20151095. Epub 2016 Aug, 8. PMID:27503072[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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