Homologous Lympho-Epithelial Kazal-type Inhibitor Domains Delay Blood Coagulation by Inhibiting Factor X and XI with Differential Specificity Ramesh, Karthik et al. Structure, Volume 26, Issue 9, 1178 - 1186.e3
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.
This work was supported by the Ministry of Education of Singapore , Academic Research Fund (AcRF) Tier 2 grant ( R-154-000-531-112 , MOE2011-T2-2-002 ) and a Tier 1 grant ( R-154-000-657-112 ) to Y.K.M. and by BMSI ( A∗STAR ) and NSCC to C.S.V. Additionally, F.T.C. has received research support from the Singapore Ministry of Education Academic Research Fund, the Singapore Immunology Network , the National Medical Research Council (NMRC; Singapore), and the Agency for Science Technology and Research (A∗STAR; Singapore; N-154-000-038-001 , R-154-000-404-112 , R-154-000-553-112 , R-154-000-565-112 , R-154-000-630-112 , R-154-000-A08–592 , R-154-000-A27-597 , SIgN-06-006 , SIgN-08-020 , and NMRC/1150/2008 ); and has received consultancy fees from the Sime Darby Technology Center, Olam International, and First Resources.
The full paper can be downloaded from the publisher's URL here: https://doi.org/10.1016/j.str.2018.05.018