Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg)
sequence changes in the signal sequence of LDL receptor

J 2016

Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor

PAVLOUŠKOVÁ, Jana; Kamila RÉBLOVÁ; Lukáš TICHÝ; Tomáš FREIBERGER; Lenka FAJKUSOVÁ et al.

Základní údaje

Originální název

Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor

Autoři

PAVLOUŠKOVÁ, Jana; Kamila RÉBLOVÁ ; Lukáš TICHÝ; Tomáš FREIBERGER a Lenka FAJKUSOVÁ

Vydání

Atherosclerosis, Clare, ELSEVIER SCI IRELAND LTD, 2016, 0021-9150

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30201 Cardiac and Cardiovascular systems

Stát vydavatele

Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.239

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/16:00087619

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

Endoplasmic reticulum; Familial hypercholesterolemia; Fluorescence microscopy; LDL; Modeling; Mutations; Signal sequence

Štítky

EL OK, podil, rivok

Změněno: 4. 1. 2017 12:33, Mgr. Eva Špillingová

Anotace

V originále

The low density lipoprotein receptor (LDLR) is a transmembrane protein that plays a key role in cholesterol metabolism. It contains 860 amino acids including a 21 amino acid long signal sequence, which directs the protein into the endoplasmic reticulum. Mutations in the LDLR gene lead to cholesterol accumulation in the plasma and results in familial hypercholesterolemia (FH). Knowledge of the impact of a mutation on the LDLR protein structure and function is very important for the diagnosis and management of FH. Unfortunately, for a large proportion of mutations this information is still missing. In this study, we focused on the LDLR signal sequence and carried out functional and in silico analyses of two sequence changes, p.(Gly20Arg) and p.(Leu15Pro), localized in this part of the LDLR. Our results revealed that the p.(Gly20Arg) change, previously described as disease causing, has no detrimental effect on protein expression or LDL particle binding. In silico analysis supports this observation, showing that both the wt and p.(Gly20Arg) signal sequences adopt an expected alpha-helix structure. In contrast, the mutation p.(Leu15Pro) is not associated with functional protein expression and exhibits a structure with disrupted a alpha-helical arrangement in the signal sequence, which most likely affects protein folding in the endoplasmic reticulum. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Návaznosti

LM2010005, projekt VaV

Název: Velká infrastruktura CESNET (Akronym: VI CESNET)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Velká infrastruktura CESNET

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

ROZV/24/LF4/2014, interní kód MU

Název: Molekulární a buněčné mechanismy patogenity mutací v genu pro LDL receptor

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Molekulární a buněčné mechanismy patogenity mutací v genu pro LDL receptor

TE02000058, projekt VaV

Název: Centrum kompetence pro molekulární diagnostiku a personalizovanou medicínu (Akronym: MOLDIMED)

Investor: Technologická agentura ČR, Centrum kompetence pro molekulární diagnostiku a personalizovanou medicínu

Přiložené soubory

1354170.pdf

Požádat o autorskou verzi souboru

Citovat

PAVLOUŠKOVÁ, Jana; Kamila RÉBLOVÁ; Lukáš TICHÝ; Tomáš FREIBERGER a Lenka FAJKUSOVÁ. Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor. Atherosclerosis. Clare: ELSEVIER SCI IRELAND LTD, 2016, roč. 250, July, s. 9-14. ISSN 0021-9150. Dostupné z: https://doi.org/10.1016/j.atherosclerosis.2016.04.022.

@article{1354170,
   author = {Pavloušková, Jana and Réblová, Kamila and Tichý, Lukáš and Freiberger, Tomáš and Fajkusová, Lenka},
   article_location = {Clare},
   article_number = {July},
   doi = {https://doi.org/10.1016/j.atherosclerosis.2016.04.022},
   keywords = {Endoplasmic reticulum; Familial hypercholesterolemia; Fluorescence microscopy; LDL; Modeling; Mutations; Signal sequence},
   language = {eng},
   issn = {0021-9150},
   journal = {Atherosclerosis},
   title = {Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor},
   url = {http://ac.els-cdn.com/S0021915016301538/1-s2.0-S0021915016301538-main.pdf?_tid=d82a03fc-7be9-11e6-964b-00000aacb360&acdnat=1474015676_ce7bba0ba82d824feeaa60145b229282},
   volume = {250},
   year = {2016}
}

TY  - JOUR
ID  - 1354170
AU  - Pavloušková, Jana - Réblová, Kamila - Tichý, Lukáš - Freiberger, Tomáš - Fajkusová, Lenka
PY  - 2016
TI  - Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor
JF  - Atherosclerosis
VL  - 250
IS  - July
SP  - 9-14
EP  - 9-14
PB  - ELSEVIER SCI IRELAND LTD
SN  - 00219150
KW  - Endoplasmic reticulum
KW  - Familial hypercholesterolemia
KW  - Fluorescence microscopy
KW  - LDL
KW  - Modeling
KW  - Mutations
KW  - Signal sequence
UR  - http://ac.els-cdn.com/S0021915016301538/1-s2.0-S0021915016301538-main.pdf?_tid=d82a03fc-7be9-11e6-964b-00000aacb360&acdnat=1474015676_ce7bba0ba82d824feeaa60145b229282
L2  - http://ac.els-cdn.com/S0021915016301538/1-s2.0-S0021915016301538-main.pdf?_tid=d82a03fc-7be9-11e6-964b-00000aacb360&acdnat=1474015676_ce7bba0ba82d824feeaa60145b229282
N2  - The low density lipoprotein receptor (LDLR) is a transmembrane protein that plays a key role in cholesterol metabolism. It contains 860 amino acids including a 21 amino acid long signal sequence, which directs the protein into the endoplasmic reticulum. Mutations in the LDLR gene lead to cholesterol accumulation in the plasma and results in familial hypercholesterolemia (FH). Knowledge of the impact of a mutation on the LDLR protein structure and function is very important for the diagnosis and management of FH. Unfortunately, for a large proportion of mutations this information is still missing. In this study, we focused on the LDLR signal sequence and carried out functional and in silico analyses of two sequence changes, p.(Gly20Arg) and p.(Leu15Pro), localized in this part of the LDLR. Our results revealed that the p.(Gly20Arg) change, previously described as disease causing, has no detrimental effect on protein expression or LDL particle binding. In silico analysis supports this observation, showing that both the wt and p.(Gly20Arg) signal sequences adopt an expected alpha-helix structure. In contrast, the mutation p.(Leu15Pro) is not associated with functional protein expression and exhibits a structure with disrupted a alpha-helical arrangement in the signal sequence, which most likely affects protein folding in the endoplasmic reticulum. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
ER  -

PAVLOUŠKOVÁ, Jana; Kamila RÉBLOVÁ; Lukáš TICHÝ; Tomáš FREIBERGER a Lenka FAJKUSOVÁ. Functional analysis of the p.(Leu15Pro) and p.(Gly20Arg) sequence changes in the signal sequence of LDL receptor. \textit{Atherosclerosis}. Clare: ELSEVIER SCI IRELAND LTD, 2016, roč.~250, July, s.~9-14. ISSN~0021-9150. Dostupné z: https://doi.org/10.1016/j.atherosclerosis.2016.04.022.

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