Structures of factor XI and prekallikrein bound to domain 6 of high–molecular weight kininogen reveal alternate domain 6 conformations and exosites

Li, Chan; Barroeta, Awital Bar; Wong, Szu Shen; Kim, Hyo Jung; Pathak, Monika; Dreveny, Ingrid; Meijers, Joost C. M.; Emsley, Jonas

doi:10.1016/j.jtha.2023.03.042

Cited by 7 publications

(4 citation statements)

References 50 publications

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“…PK and FXI, through their heavy chain, circulate bound to domain 6 of HK ( Vogel et al, 1990 ; Kunapuli et al, 1993 ). Either FXI or PK interacts via the apple domain A2 on the HK sequence (F 582 NPISDFPDT 591 ); nevertheless, in this interaction with HK, PK has the second exosite in the apple domain A1, but FXI interacts with a unique pocket formed between A2 and A3 domains ( Li et al, 2023 ).…”

Section: Functions Of the Structural Domains Of Kininogensmentioning

confidence: 99%

Human plasma kallikrein: roles in coagulation, fibrinolysis, inflammation pathways, and beyond

Motta,

Juliano,

Chagas

2023

Front. Physiol.

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Human plasma kallikrein (PKa) is obtained by activating its precursor, prekallikrein (PK), historically named the Fletcher factor. Human PKa and tissue kallikreins are serine proteases from the same family, having high- and low-molecular weight kininogens (HKs and LKs) as substrates, releasing bradykinin (Bk) and Lys-bradykinin (Lys-Bk), respectively. This review presents a brief history of human PKa with details and recent observations of its evolution among the vertebrate coagulation proteins, including the relations with Factor XI. We explored the role of Factor XII in activating the plasma kallikrein–kinin system (KKS), the mechanism of activity and control in the KKS, and the function of HK on contact activation proteins on cell membranes. The role of human PKa in cell biology regarding the contact system and KSS, particularly the endothelial cells, and neutrophils, in inflammatory processes and infectious diseases, was also approached. We examined the natural plasma protein inhibitors, including a detailed survey of human PKa inhibitors’ development and their potential market.

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Section: Functions Of the Structural Domains Of Kininogensmentioning

confidence: 99%

Human plasma kallikrein: roles in coagulation, fibrinolysis, inflammation pathways, and beyond

Motta,

Juliano,

Chagas

2023

Front. Physiol.

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“…The DFP binds to the second apple domain of coagulation factor XI and plasma kallikrein heavy chain [83]; nanobodies against factor XI apple 3 domain inhibit its protein-protein interaction, evidencing the importance of these domains [84]. These proteins are typically present in mammals and absent in plants, but coagulation factor XI and plasma kallikrein are serine proteases [85]; plant serine proteases play key roles in plant defense [86,87]. The phytoplasma effectors containing LIG_FXI_DFP_1 may target some of those proteases.…”

Section: Short Linear Motifs In Phytoplasma Effectorsmentioning

confidence: 99%

Novel Insights into Phytoplasma Effectors

Carreón-Anguiano,

Vila-Luna,

Sáenz-Carbonell

et al. 2023

Horticulturae

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Effectoromics has become integral to the identification of pathogen targets and/or host-resistant proteins for the genetic improvement of plants in agriculture and horticulture. Phytoplasmas are the causal agents of more than 100 plant diseases in economically important crops such as vegetables, spices, medicinal plants, ornamentals, palms, fruit trees, etc. To date, around 20 effectors in phytoplasmas have been experimentally validated but the list of putative effectors comprises hundreds of different proteins. Very few families (tribes) have been identified based on homology, such as the SAP05-like, SAP11-like, SAP54-like and TENGU-like families. The lack of conservation in amino acid sequences slows the progress of effectoromics in phytoplasmas since many effectors must be studied individually. Here, 717 phytoplasma effector candidates and 21 validated effectors were characterized in silico to identify common features. We identified functional domains in 153 effectors, while 585 had no known domains. The most frequently identified domain was the sequence-variable mosaic domain (SVM domain), widely distributed in 87 phytoplasma effectors. Searching for de novo amino acid motifs, 50 were found in the phytoplasma effector dataset; 696 amino acid sequences of effectors had at least 1 motif while 42 had no motif at all. These data allowed us to organize effectors into 15 tribes, uncovering, for the first time, evolutionary relationships largely masked by lack of sequence conservation among effectors. We also identified 42 eukaryotic linear motifs (ELMs) in phytoplasma effector sequences. Since the motifs are related to common functions, this novel organization of phytoplasma effectors may help further advance effectoromics research to combat phytoplasma infection in agriculture and horticulture.

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“…Plasma prekallikrein (PK) is a serine protease which circulates as a bound complex with its substrate, high-molecular-weight kininogen (HK) . PK has structural homology to factor XI (FXI), with both containing four apple domains at the N -terminus .…”

mentioning

confidence: 99%

“…Plasma prekallikrein (PK) is a serine protease which circulates as a bound complex with its substrate, high-molecular-weight kininogen (HK). 1 PK has structural homology to factor XI (FXI), with both containing four apple domains at the N -terminus. 2 The PK–HK complex in plasma 3 can be activated by a single cleavage from coagulation factor XIIa (FXIIa) resulting in the activated form, plasma kallikrein (PKa).…”

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confidence: 99%

Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein

Allison,

Davie,

Mogg

et al. 2024

ACS Med. Chem. Lett.

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Hereditary angioedema (HAE), a rare genetic disorder, is associated with uncontrolled plasma kallikrein (PKa) enzyme activity leading to the generation of bradykinin swelling in subcutaneous and submucosal membranes in various locations of the body. Herein, we describe a series of potent α-amidobenzylboronates as potential covalent inhibitors of PKa. These compounds exhibited time-dependent inhibition of PKa (compound 20 IC50 66 nM at 1 min, 70 pM at 24 h). Further compound dissociation studies demonstrated that 20 showed no apparent reversibility comparable to d-Phe-Pro-Arg-chloromethylketone (PPACK) (23), a known nonselective covalent PKa inhibitor.

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Structures of factor XI and prekallikrein bound to domain 6 of high–molecular weight kininogen reveal alternate domain 6 conformations and exosites

Cited by 7 publications

References 50 publications

Human plasma kallikrein: roles in coagulation, fibrinolysis, inflammation pathways, and beyond

Human plasma kallikrein: roles in coagulation, fibrinolysis, inflammation pathways, and beyond

Novel Insights into Phytoplasma Effectors

Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein

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