Structural insights into the activation of blood coagulation factor XI zymogen by thrombin: A computational molecular dynamics study

Shearin, Shenna; Venkateswarlu, Divi

doi:10.1016/j.bpc.2021.106737

Biophysical Chemistry

2022

DOI: 10.1016/j.bpc.2021.106737

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Structural insights into the activation of blood coagulation factor XI zymogen by thrombin: A computational molecular dynamics study

Shenna Shearin

Divi Venkateswarlu

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2024

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Cited by 2 publications

References 37 publications

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Biology of factor XI

Moellmer,

Puy,

McCarty

2024

Blood

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Unique among coagulation factors, the coagulation factor (F) XI arose through a duplication of the gene KLKB1 that encodes for plasma prekallikrein. This evolutionary origin sets FXI apart structurally as it is a homodimer with two identical subunits comprised of 4 apple and 1 catalytic domain. Each domain exhibits unique affinities for binding partners within the coagulation cascade, regulating the conversion of FXI to a serine protease as well as the selectivity of substrates cleaved by the active form of FXI. Beyond serving as the molecular nexus for the extrinsic and contact pathways to propagate thrombin generation by way of activating FIX, the function of FXI extends to contribute to barrier function, platelet activation, inflammation, and the immune response. Herein we critically review the current understanding of the molecular biology of FXI, touching on some functional consequences at the cell, tissue, and organ level. We conclude each section by highlighting the DNA mutations within each domain that present as FXI deficiency. Together, a narrative review of the structure-function of the domains of FXI is imperative to understand the etiology of Hemophilia C as well as identify regions of FXI to safely inhibit the pathological function of activation or activity of FXI without compromising the physiologic role of FXI.

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Biology of factor XI

Moellmer,

Puy,

McCarty

2024

Blood

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Case Report: Allelic and biallelic variants in coagulation factor XI cause factor XI deficiency

Liang,

Jin,

Shi

et al. 2024

Front. Cardiovasc. Med.

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Factor XI deficiency is a rare inherited coagulation disorder with an estimated prevalence of affecting 1 in 1 million. It is characterized by mild and variable bleeding phenotypes, including bruises, nosebleeds, hematuria, and postpartum hemorrhage. It can be caused by either allelic or biallelic variants in coagulation factor XI (F11). Coagulation factor XI is a glycoprotein that circulates in plasma as a non-covalent complex with high-molecular-weight kininogen. It is converted to an active protease, coagulation factor XIa, which participates in blood coagulation as a catalyst. In this study, we recruited a family with Factor XI deficiency and identified two F11 variants using whole-exome sequencing. One (NM_000128.4: c.841C>T, p.Q281X) was a known variant, and the other (NM_000128.4: c.1832T>G, p.V611G) had not been reported. In addition, we compiled the characteristics of known missense variants in coagulation factor XI. Our findings enriched the variant spectrum of Factor XI deficiency and contributed to the genetic counseling and molecular diagnostics of Factor XI deficiency.

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Structural insights into the activation of blood coagulation factor XI zymogen by thrombin: A computational molecular dynamics study

Cited by 2 publications

References 37 publications

Biology of factor XI

Biology of factor XI

Case Report: Allelic and biallelic variants in coagulation factor XI cause factor XI deficiency

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