Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
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.
In: The Journal of Biological Chemistry, Vol. 286, No. 7, 18.02.2011, p. 4951-4958.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
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