Grp78 is involved in retention of mutant low density lipoprotein receptor protein in the endoplasmic reticulum.

M M Jørgensen, Ole Nørregaard Jensen, H U Holst, J.J. Hansen, T J Corydon, P Bross, L Bolund, N Gregersen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Udgivelsesdato: 2000-Oct-27
OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind275
Udgave nummer43
Sider (fra-til)33861-8
Antal sider7
ISSN0021-9258
DOI
StatusUdgivet - 27. okt. 2000

Fingeraftryk

LDL Receptors
Proteins
Hyperlipoproteinemia Type II
Genes
Mutation
Molecular Chaperones
Liver
LDL Cholesterol
Quality control

Citer dette

Jørgensen, M M ; Jensen, Ole Nørregaard ; Holst, H U ; Hansen, J.J. ; Corydon, T J ; Bross, P ; Bolund, L ; Gregersen, N. / Grp78 is involved in retention of mutant low density lipoprotein receptor protein in the endoplasmic reticulum. I: Journal of Biological Chemistry. 2000 ; Bind 275, Nr. 43. s. 33861-8.
@article{93141ac063bd11ddb1a1000ea68e967b,
title = "Grp78 is involved in retention of mutant low density lipoprotein receptor protein in the endoplasmic reticulum.",
abstract = "The low density lipoprotein (LDL) receptor is responsible for removing the majority of the LDL cholesterol from the plasma. Mutations in the LDL receptor gene cause the disease familial hypercholesterolemia (FH). Approximately 50{\%} of the mutations in the LDL receptor gene in patients with FH lead to receptor proteins that are retained in the endoplasmic reticulum (ER). Misfolding of mutant LDL receptors is a probable cause of this ER retention, resulting in no functional LDL receptors at the cell surface. However, the specific factors and mechanisms responsible for retention of mutant LDL receptors are unknown. In the present study we show that the molecular chaperone Grp78/BiP co-immunoprecipitates with both the wild type and two different mutant (W556S and C646Y) LDL receptors in lysates obtained from human liver cells overexpressing wild type or mutant LDL receptors. A pulse-chase study shows that the interaction between the wild type LDL receptor and Grp78 is no longer detectable after 2(1/2) h, whereas it persists for more than 4 h with the mutant receptors. Furthermore, about five times more Grp78 is co-immunoprecipitated with the mutant receptors than with the wild type receptor suggesting that Grp78 is involved in retention of mutant LDL receptors in the ER. Overexpression of Grp78 causes no major alterations on the steady state level of active LDL receptors at the cell surface. However, overexpression of Grp78 decreases the processing rate of newly synthesized wild type LDL receptors. This indicates that the Grp78 interaction is a rate-limiting step in the maturation of the wild type LDL receptor and that Grp78 may be an important factor in the quality control of newly synthesized LDL receptors.",
keywords = "6-Aminonicotinamide, Amino Acid Sequence, Cells, Cultured, Endoplasmic Reticulum, HSP70 Heat-Shock Proteins, Humans, Membrane Proteins, Molecular Sequence Data, Molecular Weight, Mutation, Receptors, LDL",
author = "J{\o}rgensen, {M M} and Jensen, {Ole N{\o}rregaard} and Holst, {H U} and J.J. Hansen and Corydon, {T J} and P Bross and L Bolund and N Gregersen",
year = "2000",
month = "10",
day = "27",
doi = "10.1074/jbc.M004663200",
language = "English",
volume = "275",
pages = "33861--8",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "43",

}

Jørgensen, MM, Jensen, ON, Holst, HU, Hansen, JJ, Corydon, TJ, Bross, P, Bolund, L & Gregersen, N 2000, 'Grp78 is involved in retention of mutant low density lipoprotein receptor protein in the endoplasmic reticulum.', Journal of Biological Chemistry, bind 275, nr. 43, s. 33861-8. https://doi.org/10.1074/jbc.M004663200

Grp78 is involved in retention of mutant low density lipoprotein receptor protein in the endoplasmic reticulum. / Jørgensen, M M; Jensen, Ole Nørregaard; Holst, H U; Hansen, J.J.; Corydon, T J; Bross, P; Bolund, L; Gregersen, N.

I: Journal of Biological Chemistry, Bind 275, Nr. 43, 27.10.2000, s. 33861-8.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Grp78 is involved in retention of mutant low density lipoprotein receptor protein in the endoplasmic reticulum.

AU - Jørgensen, M M

AU - Jensen, Ole Nørregaard

AU - Holst, H U

AU - Hansen, J.J.

AU - Corydon, T J

AU - Bross, P

AU - Bolund, L

AU - Gregersen, N

PY - 2000/10/27

Y1 - 2000/10/27

N2 - The low density lipoprotein (LDL) receptor is responsible for removing the majority of the LDL cholesterol from the plasma. Mutations in the LDL receptor gene cause the disease familial hypercholesterolemia (FH). Approximately 50% of the mutations in the LDL receptor gene in patients with FH lead to receptor proteins that are retained in the endoplasmic reticulum (ER). Misfolding of mutant LDL receptors is a probable cause of this ER retention, resulting in no functional LDL receptors at the cell surface. However, the specific factors and mechanisms responsible for retention of mutant LDL receptors are unknown. In the present study we show that the molecular chaperone Grp78/BiP co-immunoprecipitates with both the wild type and two different mutant (W556S and C646Y) LDL receptors in lysates obtained from human liver cells overexpressing wild type or mutant LDL receptors. A pulse-chase study shows that the interaction between the wild type LDL receptor and Grp78 is no longer detectable after 2(1/2) h, whereas it persists for more than 4 h with the mutant receptors. Furthermore, about five times more Grp78 is co-immunoprecipitated with the mutant receptors than with the wild type receptor suggesting that Grp78 is involved in retention of mutant LDL receptors in the ER. Overexpression of Grp78 causes no major alterations on the steady state level of active LDL receptors at the cell surface. However, overexpression of Grp78 decreases the processing rate of newly synthesized wild type LDL receptors. This indicates that the Grp78 interaction is a rate-limiting step in the maturation of the wild type LDL receptor and that Grp78 may be an important factor in the quality control of newly synthesized LDL receptors.

AB - The low density lipoprotein (LDL) receptor is responsible for removing the majority of the LDL cholesterol from the plasma. Mutations in the LDL receptor gene cause the disease familial hypercholesterolemia (FH). Approximately 50% of the mutations in the LDL receptor gene in patients with FH lead to receptor proteins that are retained in the endoplasmic reticulum (ER). Misfolding of mutant LDL receptors is a probable cause of this ER retention, resulting in no functional LDL receptors at the cell surface. However, the specific factors and mechanisms responsible for retention of mutant LDL receptors are unknown. In the present study we show that the molecular chaperone Grp78/BiP co-immunoprecipitates with both the wild type and two different mutant (W556S and C646Y) LDL receptors in lysates obtained from human liver cells overexpressing wild type or mutant LDL receptors. A pulse-chase study shows that the interaction between the wild type LDL receptor and Grp78 is no longer detectable after 2(1/2) h, whereas it persists for more than 4 h with the mutant receptors. Furthermore, about five times more Grp78 is co-immunoprecipitated with the mutant receptors than with the wild type receptor suggesting that Grp78 is involved in retention of mutant LDL receptors in the ER. Overexpression of Grp78 causes no major alterations on the steady state level of active LDL receptors at the cell surface. However, overexpression of Grp78 decreases the processing rate of newly synthesized wild type LDL receptors. This indicates that the Grp78 interaction is a rate-limiting step in the maturation of the wild type LDL receptor and that Grp78 may be an important factor in the quality control of newly synthesized LDL receptors.

KW - 6-Aminonicotinamide

KW - Amino Acid Sequence

KW - Cells, Cultured

KW - Endoplasmic Reticulum

KW - HSP70 Heat-Shock Proteins

KW - Humans

KW - Membrane Proteins

KW - Molecular Sequence Data

KW - Molecular Weight

KW - Mutation

KW - Receptors, LDL

U2 - 10.1074/jbc.M004663200

DO - 10.1074/jbc.M004663200

M3 - Journal article

VL - 275

SP - 33861

EP - 33868

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 43

ER -