How the Linker Connecting the Two Kringles Influences Activation and Conformational Plasticity of Prothrombin.

The Journal of Biological Chemistry
Nicola PozziEnrico Di Cera

Abstract

A flexible linker (Lnk2) composed of 26 amino acids connects kringle-1 to kringle-2 in the coagulation factor prothrombin. Recent studies point to Lnk2 as a key determinant of the structure and function of this zymogen. Using a combination of mutagenesis, structural biology, and single molecule spectroscopy, we show how Lnk2 influences activation and conformational plasticity of prothrombin. Scrambling the sequence of Lnk2 is inconsequential on activation, and so is extension by as many as 22 residues. On the other hand, below a critical length of 15 residues, the rate of prothrombin activation increases (10-fold) in the absence of cofactor Va and decreases (3-fold) in the presence of cofactor. Furthermore, activation by prothrombinase takes place without preference along the prethrombin-2 (cleavage at Arg(271) first) or meizothrombin (cleavage at Arg(320) first) pathways. Notably, these transitions in the rate and pathway of activation require the presence of phospholipids, pointing to an important physiological role for Lnk2 when prothrombin is anchored to the membrane. Two new crystal structures of prothrombin lacking 22 (ProTΔ146-167) or 14 (ProTΔ154-167) residues of Lnk2 document striking conformational rearrangements of d...Continue Reading

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Citations

Jul 1, 2016·Journal of Thrombosis and Haemostasis : JTH·N Pozzi, E Di Cera
May 19, 2017·Journal of Cellular Biochemistry·Reyhaneh RabieianHamed Mirzaei
Feb 15, 2018·Scientific Reports·Mathivanan ChinnarajNicola Pozzi
Mar 8, 2018·Scientific Reports·Pradipta ChakrabortyEnrico Di Cera
Jul 4, 2019·Anais Da Academia Brasileira De Ciências·Tamara R MarquesAngelita D Corrêa
Aug 25, 2019·Scientific Reports·Leslie A PelcEnrico Di Cera
Jul 21, 2016·The Journal of Biological Chemistry·Nicola PozziEnrico Di Cera
Apr 18, 2019·Scientific Reports·Laura AcquasalienteEnrico Di Cera
Mar 14, 2019·Biomolecular Concepts·Bosko M StojanovskiEnrico Di Cera
Aug 29, 2020·The Journal of Biological Chemistry·Bosko M StojanovskiEnrico Di Cera
Jul 16, 2021·The Journal of Biological Chemistry·Bosko M Stojanovski, Enrico Di Cera

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