DOI: 10.1083/jcb.200304014. Different cofactor activities in γ-secretase assembly [Penn]

Different cofactor activities in γ-secretase assembly

10.1083/jcb.200304014

Crossref journal-article

Rockefeller University Press

The Journal of Cell Biology (291)

Abstract

The γ-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative γ-secretase components have been identified—presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we use a stepwise coexpression approach to investigate the role of each new component in γ-secretase assembly and activation. Coexpression of all four proteins leads to high level accumulation of mature Psn and increased proteolysis of Notch. Aph-1 and Nct may form a subcomplex that stabilizes the Psn holoprotein at an early step in γ-secretase assembly. Subcomplex levels of Aph-1 are down-regulated by stepwise addition of Psn, suggesting that Aph-1 might not enter the mature complex. In contrast, Pen-2 accumulates proportionally with Psn, and is associated with Psn endoproteolysis during γ-secretase assembly. These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in γ-secretase assembly and activation.

Bibliography

Hu, Y., & Fortini, M. E. (2003). Different cofactor activities in Î³-secretase assembly. The Journal of Cell Biology, 161(4), 685â690.

Authors 2

Yue Hu (first)
Mark E. Fortini (additional)

References 24 Referenced 109

10.1038/35087069 / Nat. Cell Biol. (2001)
10.1038/ncb1201-1129 / Nat. Cell Biol. (2001)
10.1016/0092-8674(93)90356-U / Cell. (1993)
10.1038/ncb960 / Nat. Cell Biol. (2003)
10.1016/S1534-5807(02)00189-2 / Dev. Cell. (2002)
10.1073/pnas.022523499 / Proc. Natl. Acad. Sci. USA. (2002)
10.1074/jbc.M209499200 / J. Biol. Chem. (2003)
10.1016/S1534-5807(01)00105-8 / Dev. Cell. (2002)
10.1101/gad.836900 / Genes Dev. (2000)
10.1074/jbc.M208164200 / J. Biol. Chem. (2002)
10.1073/pnas.211321898 / Proc. Natl. Acad. Sci. USA. (2001)
10.1093/genetics/138.1.111 / Genetics. (1994)
10.1016/S1534-5807(01)00109-5 / Dev. Cell. (2002)
10.1074/jbc.C200648200 / J. Biol. Chem. (2003)
10.1074/jbc.272.39.24536 / J. Biol. Chem. (1997)
10.1038/nrn785 / Nat. Rev. Neurosci. (2002)
10.1074/jbc.C200469200 / J. Biol. Chem. (2002)
10.1038/19091 / Nature. (1999)
10.1038/nature01506 / Nature. (2003)
10.1016/S0896-6273(00)80291-3 / Neuron. (1996)
10.1074/jbc.272.45.28415 / J. Biol. Chem. (1997)
10.1016/S0925-4773(98)00169-5 / Mech. Dev. (1998)
10.1038/19096 / Nature. (1999)
10.1038/35024009 / Nature. (2000)

Dates

Type	When
Created	22 years, 3 months ago (May 27, 2003, 1:45 p.m.)
Deposited	2 years, 1 month ago (July 22, 2023, 10:15 a.m.)
Indexed	1 year ago (Aug. 5, 2024, 4:33 a.m.)
Issued	22 years, 3 months ago (May 26, 2003)
Published	22 years, 3 months ago (May 26, 2003)
Published Online	22 years, 3 months ago (May 27, 2003)
Published Print	22 years, 3 months ago (May 26, 2003)

Funders 0

None

BibTeX

@article{Hu_2003, title={Different cofactor activities in γ-secretase assembly}, volume={161}, ISSN={0021-9525}, url={http://dx.doi.org/10.1083/jcb.200304014}, DOI={10.1083/jcb.200304014}, number={4}, journal={The Journal of Cell Biology}, publisher={Rockefeller University Press}, author={Hu, Yue and Fortini, Mark E.}, year={2003}, month=may, pages={685–690} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2024,
        8,
        5
      ]
    ],
    "date-time": "2024-08-05T08:33:30Z",
    "timestamp": 1722846810968
  },
  "reference-count": 24,
  "publisher": "Rockefeller University Press",
  "issue": "4",
  "content-domain": {
    "domain": [
      "rupress.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2003,
        5,
        26
      ]
    ]
  },
  "abstract": "<jats:p>The \u03b3-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative \u03b3-secretase components have been identified\u2014presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we use a stepwise coexpression approach to investigate the role of each new component in \u03b3-secretase assembly and activation. Coexpression of all four proteins leads to high level accumulation of mature Psn and increased proteolysis of Notch. Aph-1 and Nct may form a subcomplex that stabilizes the Psn holoprotein at an early step in \u03b3-secretase assembly. Subcomplex levels of Aph-1 are down-regulated by stepwise addition of Psn, suggesting that Aph-1 might not enter the mature complex. In contrast, Pen-2 accumulates proportionally with Psn, and is associated with Psn endoproteolysis during \u03b3-secretase assembly. These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in \u03b3-secretase assembly and activation.</jats:p>",
  "DOI": "10.1083/jcb.200304014",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2003,
        5,
        27
      ]
    ],
    "date-time": "2003-05-27T17:45:39Z",
    "timestamp": 1054057539000
  },
  "page": "685-690",
  "update-policy": "http://dx.doi.org/10.1083/jcb.crossmarkpolicy",
  "source": "Crossref",
  "is-referenced-by-count": 109,
  "title": "Different cofactor activities in \u03b3-secretase assembly",
  "prefix": "10.1083",
  "volume": "161",
  "author": [
    {
      "given": "Yue",
      "family": "Hu",
      "sequence": "first",
      "affiliation": [
        {
          "name": "1University of Pennsylvania School of Medicine, Philadelphia, PA 19104"
        }
      ]
    },
    {
      "given": "Mark E.",
      "family": "Fortini",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "2National Cancer Institute, Frederick, MD 21702"
        }
      ]
    }
  ],
  "member": "291",
  "published-online": {
    "date-parts": [
      [
        2003,
        5,
        27
      ]
    ]
  },
  "reference": [
    {
      "key": "2023072214145786200_BIB1",
      "doi-asserted-by": "crossref",
      "first-page": "751",
      "DOI": "10.1038/35087069",
      "volume": "3",
      "year": "2001",
      "journal-title": "Nat. Cell Biol."
    },
    {
      "key": "2023072214145786200_BIB2",
      "doi-asserted-by": "crossref",
      "first-page": "1129",
      "DOI": "10.1038/ncb1201-1129",
      "volume": "3",
      "year": "2001",
      "journal-title": "Nat. Cell Biol."
    },
    {
      "key": "2023072214145786200_BIB3",
      "doi-asserted-by": "crossref",
      "first-page": "1281",
      "DOI": "10.1016/0092-8674(93)90356-U",
      "volume": "73",
      "year": "1993",
      "journal-title": "Cell."
    },
    {
      "key": "2023072214145786200_BIB4",
      "doi-asserted-by": "crossref",
      "first-page": "486",
      "DOI": "10.1038/ncb960",
      "volume": "5",
      "year": "2003",
      "journal-title": "Nat. Cell Biol."
    },
    {
      "key": "2023072214145786200_BIB5",
      "doi-asserted-by": "crossref",
      "first-page": "85",
      "DOI": "10.1016/S1534-5807(02)00189-2",
      "volume": "3",
      "year": "2002",
      "journal-title": "Dev. Cell."
    },
    {
      "key": "2023072214145786200_BIB6",
      "doi-asserted-by": "crossref",
      "first-page": "775",
      "DOI": "10.1073/pnas.022523499",
      "volume": "99",
      "year": "2002",
      "journal-title": "Proc. Natl. Acad. Sci. USA."
    },
    {
      "key": "2023072214145786200_BIB7",
      "doi-asserted-by": "crossref",
      "first-page": "7374",
      "DOI": "10.1074/jbc.M209499200",
      "volume": "278",
      "year": "2003",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2023072214145786200_BIB8",
      "doi-asserted-by": "crossref",
      "first-page": "69",
      "DOI": "10.1016/S1534-5807(01)00105-8",
      "volume": "2",
      "year": "2002",
      "journal-title": "Dev. Cell."
    },
    {
      "key": "2023072214145786200_BIB9",
      "doi-asserted-by": "crossref",
      "first-page": "2799",
      "DOI": "10.1101/gad.836900",
      "volume": "14",
      "year": "2000",
      "journal-title": "Genes Dev."
    },
    {
      "key": "2023072214145786200_BIB10",
      "doi-asserted-by": "crossref",
      "first-page": "45013",
      "DOI": "10.1074/jbc.M208164200",
      "volume": "277",
      "year": "2002",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2023072214145786200_BIB11",
      "doi-asserted-by": "crossref",
      "first-page": "12186",
      "DOI": "10.1073/pnas.211321898",
      "volume": "98",
      "year": "2001",
      "journal-title": "Proc. Natl. Acad. Sci. USA."
    },
    {
      "key": "2023072214145786200_BIB12",
      "doi-asserted-by": "crossref",
      "first-page": "111",
      "DOI": "10.1093/genetics/138.1.111",
      "volume": "138",
      "year": "1994",
      "journal-title": "Genetics."
    },
    {
      "key": "2023072214145786200_BIB13",
      "doi-asserted-by": "crossref",
      "first-page": "79",
      "DOI": "10.1016/S1534-5807(01)00109-5",
      "volume": "2",
      "year": "2002",
      "journal-title": "Dev. Cell."
    },
    {
      "key": "2023072214145786200_BIB14",
      "doi-asserted-by": "crossref",
      "first-page": "7850",
      "DOI": "10.1074/jbc.C200648200",
      "volume": "278",
      "year": "2003",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2023072214145786200_BIB15",
      "doi-asserted-by": "crossref",
      "first-page": "24536",
      "DOI": "10.1074/jbc.272.39.24536",
      "volume": "272",
      "year": "1997",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2023072214145786200_BIB16",
      "doi-asserted-by": "crossref",
      "first-page": "281",
      "DOI": "10.1038/nrn785",
      "volume": "3",
      "year": "2002",
      "journal-title": "Nat. Rev. Neurosci."
    },
    {
      "key": "2023072214145786200_BIB17",
      "doi-asserted-by": "crossref",
      "first-page": "39062",
      "DOI": "10.1074/jbc.C200469200",
      "volume": "277",
      "year": "2002",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2023072214145786200_BIB18",
      "doi-asserted-by": "crossref",
      "first-page": "522",
      "DOI": "10.1038/19091",
      "volume": "398",
      "year": "1999",
      "journal-title": "Nature."
    },
    {
      "key": "2023072214145786200_BIB19",
      "doi-asserted-by": "crossref",
      "first-page": "438",
      "DOI": "10.1038/nature01506",
      "volume": "422",
      "year": "2003",
      "journal-title": "Nature."
    },
    {
      "key": "2023072214145786200_BIB20",
      "doi-asserted-by": "crossref",
      "first-page": "181",
      "DOI": "10.1016/S0896-6273(00)80291-3",
      "volume": "17",
      "year": "1996",
      "journal-title": "Neuron."
    },
    {
      "key": "2023072214145786200_BIB21",
      "doi-asserted-by": "crossref",
      "first-page": "28415",
      "DOI": "10.1074/jbc.272.45.28415",
      "volume": "272",
      "year": "1997",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "2023072214145786200_BIB22",
      "doi-asserted-by": "crossref",
      "first-page": "199",
      "DOI": "10.1016/S0925-4773(98)00169-5",
      "volume": "79",
      "year": "1998",
      "journal-title": "Mech. Dev."
    },
    {
      "key": "2023072214145786200_BIB23",
      "doi-asserted-by": "crossref",
      "first-page": "525",
      "DOI": "10.1038/19096",
      "volume": "398",
      "year": "1999",
      "journal-title": "Nature."
    },
    {
      "key": "2023072214145786200_BIB24",
      "doi-asserted-by": "crossref",
      "first-page": "48",
      "DOI": "10.1038/35024009",
      "volume": "407",
      "year": "2000",
      "journal-title": "Nature."
    }
  ],
  "container-title": "The Journal of Cell Biology",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://rupress.org/jcb/article-pdf/161/4/685/1523282/jcb1614685.pdf",
      "content-type": "application/pdf",
      "content-version": "vor",
      "intended-application": "syndication"
    },
    {
      "URL": "https://rupress.org/jcb/article-pdf/161/4/685/1523282/jcb1614685.pdf",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        7,
        22
      ]
    ],
    "date-time": "2023-07-22T14:15:27Z",
    "timestamp": 1690035327000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://rupress.org/jcb/article/161/4/685/44015/Different-cofactor-activities-in-secretase"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2003,
        5,
        26
      ]
    ]
  },
  "references-count": 24,
  "journal-issue": {
    "issue": "4",
    "published-print": {
      "date-parts": [
        [
          2003,
          5,
          26
        ]
      ]
    }
  },
  "URL": "http://dx.doi.org/10.1083/jcb.200304014",
  "relation": {},
  "ISSN": [
    "1540-8140",
    "0021-9525"
  ],
  "subject": [],
  "published": {
    "date-parts": [
      [
        2003,
        5,
        26
      ]
    ]
  }
}