title: Fluorescent Analogue of Batimastat Enables Imaging of α-Secretase in Living Cells.
abstract: The ADAM family of metalloproteases cleave a diverse range of transmembrane substrates, resulting in the release of their soluble ectodomains. This process of protein shedding, termed α-secretase processing, is involved in many facets of both normal and disease related cellular function. While the processing of substrates has been well documented, the regulation and trafficking of the ADAMs are less well understood. Tools that allow for the study of ADAMs under their native environment will allow for a better understanding of their regulation and activity. Here we describe the design and evaluation of a novel fluorescent analogue of a well-characterized ADAM inhibitor, Batimastat. This probe exhibited similar activity for inhibiting α-secretase processing in cells as did Batimastat. Importantly, this probe specifically labeled ADAMs fluorescently in both fixed and living cells, enabling the possibility to study the trafficking of α-secretase proteins in a dynamic environment.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego , La Jolla, California 92093-0358, United States.
authors.forename: Geoffray
authors.initials: G
authors.lastname: Leriche
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Chen
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Sumin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego , La Jolla, California 92093-0358, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Yang
mesh_terms: D051722:ADAM Proteins / Q000187:drug effects / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D008562:Membrane Glycoproteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D013876:Thiophenes; C413604:nicastrin protein; D010649:Phenylalanine; C080985:batimastat; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins
keywords: ADAMs; fluorescence; live-cell imaging; probe; α-secretase