Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity
Despite being initially identified in the blood filtrate, LEKTI is a 15-domain Kazal-type inhibitor mostly known in the regulation of skin desquamation. In the current study, screening of serine proteases in blood coagulation cascade showed that LEKTI domain 4 has inhibitory activity toward only FXI...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2020
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| Online Access: | https://hdl.handle.net/10356/140346 |
| _version_ | 1824455713453244416 |
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| author | Ramesh, Karthik Lama, Dilraj Tan, Kang Wei Nguyen, Van Sang Chew, Fook Tim Verma, Chandra Shekhar Mok, Yu Keung |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Ramesh, Karthik Lama, Dilraj Tan, Kang Wei Nguyen, Van Sang Chew, Fook Tim Verma, Chandra Shekhar Mok, Yu Keung |
| author_sort | Ramesh, Karthik |
| collection | NTU |
| description | Despite being initially identified in the blood filtrate, LEKTI is a 15-domain Kazal-type inhibitor mostly known in the regulation of skin desquamation. In the current study, screening of serine proteases in blood coagulation cascade showed that LEKTI domain 4 has inhibitory activity toward only FXIa, whereas LEKTI domain 6 inhibits both FXIa and FXaB (bovine FXa). Nuclear magnetic resonance structural and dynamic experiments plus molecular dynamics simulation revealed that LEKTI domain 4 has enhanced backbone flexibility at the reactive-site loop. A model of the LEKTI-protease complex revealed that FXaB has a narrower S4 pocket compared with FXIa and hence prefers only small side-chain residues at the P4 position, such as Ala in LEKTI domain 6. Mutational studies combined with a molecular complex model suggest that both a more flexible reactive-site loop and a bulky residue at the P4 position make LEKTI domain 4 a weaker but highly selective inhibitor of FXIa. |
| first_indexed | 2025-02-19T03:42:35Z |
| format | Journal Article |
| id | ntu-10356/140346 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:42:35Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1403462020-05-28T04:24:06Z Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity Ramesh, Karthik Lama, Dilraj Tan, Kang Wei Nguyen, Van Sang Chew, Fook Tim Verma, Chandra Shekhar Mok, Yu Keung School of Biological Sciences Science::Biological sciences Lympho-epithelial Kazal-type related inhibitor Factor Xa Despite being initially identified in the blood filtrate, LEKTI is a 15-domain Kazal-type inhibitor mostly known in the regulation of skin desquamation. In the current study, screening of serine proteases in blood coagulation cascade showed that LEKTI domain 4 has inhibitory activity toward only FXIa, whereas LEKTI domain 6 inhibits both FXIa and FXaB (bovine FXa). Nuclear magnetic resonance structural and dynamic experiments plus molecular dynamics simulation revealed that LEKTI domain 4 has enhanced backbone flexibility at the reactive-site loop. A model of the LEKTI-protease complex revealed that FXaB has a narrower S4 pocket compared with FXIa and hence prefers only small side-chain residues at the P4 position, such as Ala in LEKTI domain 6. Mutational studies combined with a molecular complex model suggest that both a more flexible reactive-site loop and a bulky residue at the P4 position make LEKTI domain 4 a weaker but highly selective inhibitor of FXIa. ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) NMRC (Natl Medical Research Council, S’pore) 2020-05-28T04:24:05Z 2020-05-28T04:24:05Z 2018 Journal Article Ramesh, K., Lama, D., Tan, K. W., Nguyen, V. S., Chew, F. T., Verma, C. S., & Mok, Y. K. (2018). Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity. Structure, 26(9), 1178-1186. doi:10.1016/j.str.2018.05.018 0969-2126 https://hdl.handle.net/10356/140346 10.1016/j.str.2018.05.018 30017565 2-s2.0-85048426620 9 26 1178 1186 en Structure © 2018 Elsevier Ltd. All rights reserved. |
| spellingShingle | Science::Biological sciences Lympho-epithelial Kazal-type related inhibitor Factor Xa Ramesh, Karthik Lama, Dilraj Tan, Kang Wei Nguyen, Van Sang Chew, Fook Tim Verma, Chandra Shekhar Mok, Yu Keung Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity |
| title | Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity |
| title_full | Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity |
| title_fullStr | Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity |
| title_full_unstemmed | Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity |
| title_short | Homologous Lympho-epithelial Kazal-type inhibitor domains delay blood coagulation by inhibiting factor X and XI with differential specificity |
| title_sort | homologous lympho epithelial kazal type inhibitor domains delay blood coagulation by inhibiting factor x and xi with differential specificity |
| topic | Science::Biological sciences Lympho-epithelial Kazal-type related inhibitor Factor Xa |
| url | https://hdl.handle.net/10356/140346 |
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