Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp

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Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp. / Runager, Kasper; Basaiawmoit, Rajiv Vaid; Deva, Taru; Andreasen, Maria; Valnickova, Zuzana; Sørensen, Charlotte S; Karring, Henrik; Thøgersen, Ida B; Christiansen, Gunna; Underhaug, Jarl; Kristensen, Torsten; Nielsen, Niels Chr; Klintworth, Gordon K; Otzen, Daniel E; Enghild, Jan J.

I: The Journal of Biological Chemistry, Bind 286, Nr. 7, 18.02.2011, s. 4951-4958.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Runager, K, Basaiawmoit, RV, Deva, T, Andreasen, M, Valnickova, Z, Sørensen, CS, Karring, H, Thøgersen, IB, Christiansen, G, Underhaug, J, Kristensen, T, Nielsen, NC, Klintworth, GK, Otzen, DE & Enghild, JJ 2011, 'Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp', The Journal of Biological Chemistry, bind 286, nr. 7, s. 4951-4958. https://doi.org/10.1074/jbc.M110.181099

APA

Runager, K., Basaiawmoit, R. V., Deva, T., Andreasen, M., Valnickova, Z., Sørensen, C. S., ... Enghild, J. J. (2011). Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp. The Journal of Biological Chemistry, 286(7), 4951-4958. https://doi.org/10.1074/jbc.M110.181099

Vancouver

Runager K, Basaiawmoit RV, Deva T, Andreasen M, Valnickova Z, Sørensen CS o.a. Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp. The Journal of Biological Chemistry. 2011 feb 18;286(7):4951-4958. https://doi.org/10.1074/jbc.M110.181099

Author

Runager, Kasper ; Basaiawmoit, Rajiv Vaid ; Deva, Taru ; Andreasen, Maria ; Valnickova, Zuzana ; Sørensen, Charlotte S ; Karring, Henrik ; Thøgersen, Ida B ; Christiansen, Gunna ; Underhaug, Jarl ; Kristensen, Torsten ; Nielsen, Niels Chr ; Klintworth, Gordon K ; Otzen, Daniel E ; Enghild, Jan J. / Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp. I: The Journal of Biological Chemistry. 2011 ; Bind 286, Nr. 7. s. 4951-4958.

Bibtex

@article{225401390fb44dd9a9909f092500b7c3,
title = "Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp",
abstract = "Mutations in the human TGFBI gene encoding TGFBIp have been linked to protein deposits in the cornea leading to visual impairment. The protein consists of an N-terminal Cys-rich EMI domain and four consecutive fasciclin 1 (FAS1) domains. We have compared the stabilities of wild-type (WT) human TGFBIp and six mutants known to produce phenotypically distinct deposits in the cornea. Amino acid substitutions in the first FAS1 (FAS1-1) domain (R124H, R124L, and R124C) did not alter the stability. However, substitutions within the fourth FAS1 (FAS1-4) domain (A546T, R555Q, and R555W) affected the overall stability of intact TGFBIp revealing the following stability ranking R555W>WT>R555Q>A546T. Significantly, the stability ranking of the isolated FAS1-4 domains mirrored the behavior of the intact protein. In addition, it was linked to the aggregation propensity as the least stable mutant (A546T) forms amyloid fibrils while the more stable variants generate non-amyloid amorphous deposits in vivo. Significantly, the data suggested that both an increase and a decrease in the stability of FAS1-4 may unleash a disease mechanism. In contrast, amino acid substitutions in FAS1-1 did not affect the stability of the intact TGFBIp suggesting that molecular the mechanism of disease differs depending on the FAS1 domain carrying the mutation.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Kasper Runager and Basaiawmoit, {Rajiv Vaid} and Taru Deva and Maria Andreasen and Zuzana Valnickova and S{\o}rensen, {Charlotte S} and Henrik Karring and Th{\o}gersen, {Ida B} and Gunna Christiansen and Jarl Underhaug and Torsten Kristensen and Nielsen, {Niels Chr} and Klintworth, {Gordon K} and Otzen, {Daniel E} and Enghild, {Jan J}",
year = "2011",
month = "2",
day = "18",
doi = "10.1074/jbc.M110.181099",
language = "English",
volume = "286",
pages = "4951--4958",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "7",

}

RIS

TY - JOUR

T1 - Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp

AU - Runager, Kasper

AU - Basaiawmoit, Rajiv Vaid

AU - Deva, Taru

AU - Andreasen, Maria

AU - Valnickova, Zuzana

AU - Sørensen, Charlotte S

AU - Karring, Henrik

AU - Thøgersen, Ida B

AU - Christiansen, Gunna

AU - Underhaug, Jarl

AU - Kristensen, Torsten

AU - Nielsen, Niels Chr

AU - Klintworth, Gordon K

AU - Otzen, Daniel E

AU - Enghild, Jan J

PY - 2011/2/18

Y1 - 2011/2/18

N2 - Mutations in the human TGFBI gene encoding TGFBIp have been linked to protein deposits in the cornea leading to visual impairment. The protein consists of an N-terminal Cys-rich EMI domain and four consecutive fasciclin 1 (FAS1) domains. We have compared the stabilities of wild-type (WT) human TGFBIp and six mutants known to produce phenotypically distinct deposits in the cornea. Amino acid substitutions in the first FAS1 (FAS1-1) domain (R124H, R124L, and R124C) did not alter the stability. However, substitutions within the fourth FAS1 (FAS1-4) domain (A546T, R555Q, and R555W) affected the overall stability of intact TGFBIp revealing the following stability ranking R555W>WT>R555Q>A546T. Significantly, the stability ranking of the isolated FAS1-4 domains mirrored the behavior of the intact protein. In addition, it was linked to the aggregation propensity as the least stable mutant (A546T) forms amyloid fibrils while the more stable variants generate non-amyloid amorphous deposits in vivo. Significantly, the data suggested that both an increase and a decrease in the stability of FAS1-4 may unleash a disease mechanism. In contrast, amino acid substitutions in FAS1-1 did not affect the stability of the intact TGFBIp suggesting that molecular the mechanism of disease differs depending on the FAS1 domain carrying the mutation.

AB - Mutations in the human TGFBI gene encoding TGFBIp have been linked to protein deposits in the cornea leading to visual impairment. The protein consists of an N-terminal Cys-rich EMI domain and four consecutive fasciclin 1 (FAS1) domains. We have compared the stabilities of wild-type (WT) human TGFBIp and six mutants known to produce phenotypically distinct deposits in the cornea. Amino acid substitutions in the first FAS1 (FAS1-1) domain (R124H, R124L, and R124C) did not alter the stability. However, substitutions within the fourth FAS1 (FAS1-4) domain (A546T, R555Q, and R555W) affected the overall stability of intact TGFBIp revealing the following stability ranking R555W>WT>R555Q>A546T. Significantly, the stability ranking of the isolated FAS1-4 domains mirrored the behavior of the intact protein. In addition, it was linked to the aggregation propensity as the least stable mutant (A546T) forms amyloid fibrils while the more stable variants generate non-amyloid amorphous deposits in vivo. Significantly, the data suggested that both an increase and a decrease in the stability of FAS1-4 may unleash a disease mechanism. In contrast, amino acid substitutions in FAS1-1 did not affect the stability of the intact TGFBIp suggesting that molecular the mechanism of disease differs depending on the FAS1 domain carrying the mutation.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1074/jbc.M110.181099

DO - 10.1074/jbc.M110.181099

M3 - Journal article

C2 - 21135107

VL - 286

SP - 4951

EP - 4958

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 7

ER -

ID: 35937068