Factor XII Explored with AlphaFold - Opportunities for Selective Drug Development

Frunt, Rowan; Otmani, Hinde El; Kaira, Bubacarr G; Maat, Steven de; Maas, Coen

doi:10.1055/a-1951-1777

Cited by 5 publications

(5 citation statements)

References 59 publications

(86 reference statements)

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“…Models of FXII generated with AlphaFold suggest there are complex interactions between domains that would not be revealed by crystal structures of isolated domains or even multidomain fragments. 54 The complexity of the properly folded molecule raises the possibility that studies with recombinant deletion variants may not be optimal for assessing certain FXII structure–function relationships. Similarly, individual isolated domains removed from the context of the whole molecule may not retain normal activity or may produce artifact.…”

Section: Discussionmentioning

confidence: 99%

“…20 Our analysis indicates that a series of lysine residues at the N-terminus of the EGF1 domain play a key role in binding to polyanions such as polyphosphate, heparin, and dextran sulfate. In addition to supporting binding, EGF1 may function as a switch that is triggered by binding, 54 leading to disruption of interactions involving the KNG and FN2 domains that maintain the closed conformation. In aPTT assays, particles of silica are often used to induce contact activation to drive clot formation.…”

Section: A Model For Fxii Activation and Activitymentioning

confidence: 99%

“…2,3 The Factor XII Molecule Human FXII is an 80-kDa polypeptide with a plasma concentration of 30 μg/mL (375 nM). 1,3,[53][54][55] Most plasma FXII is synthesized in hepatocytes, but the protein is expressed in other tissues including leukocytes. 56 The diagram in ►Fig.…”

Section: Disease Processes Involving the Kallikrein-kinin Systemmentioning

confidence: 99%

“…Crystal structures for the protease domain [59][60][61] and fragments of the heavy chain [62][63][64] have been reported, and structures for individual domains (except for the PRR) may be predicted based on homology with other proteins. In a predicted structure for the whole FXII molecule generated by the artificial intelligence-based program AlphaFold, 54,65 domains within the FXII non-catalytic heavy chain region fold into a structure with the FN2 domain and KNG domain approximated (►Fig. 3B).…”

Section: Disease Processes Involving the Kallikrein-kinin Systemmentioning

confidence: 99%

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Factor XII Structure–Function Relationships

Shamanaev

Litvak

Ivanov

et al. 2023

Semin Thromb Hemost

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Factor XII (FXII), the zymogen of the protease FXIIa, contributes to pathologic processes such as bradykinin-dependent angioedema and thrombosis through its capacity to convert the homologs prekallikrein and factor XI to the proteases plasma kallikrein and factor XIa. FXII activation and FXIIa activity are enhanced when the protein binds to a surface. Here, we review recent work on the structure and enzymology of FXII with an emphasis on how they relate to pathology. FXII is a homolog of pro-hepatocyte growth factor activator (pro-HGFA). We prepared a panel of FXII molecules in which individual domains were replaced with corresponding pro-HGFA domains and tested them in FXII activation and activity assays. When in fluid phase (not surface bound), FXII and prekallikrein undergo reciprocal activation. The FXII heavy chain restricts reciprocal activation, setting limits on the rate of this process. Pro-HGFA replacements for the FXII fibronectin type 2 or kringle domains markedly accelerate reciprocal activation, indicating disruption of the normal regulatory function of the heavy chain. Surface binding also enhances FXII activation and activity. This effect is lost if the FXII first epidermal growth factor (EGF1) domain is replaced with pro-HGFA EGF1. These results suggest that FXII circulates in blood in a “closed” form that is resistant to activation. Intramolecular interactions involving the fibronectin type 2 and kringle domains maintain the closed form. FXII binding to a surface through the EGF1 domain disrupts these interactions, resulting in an open conformation that facilitates FXII activation. These observations have implications for understanding FXII contributions to diseases such as hereditary angioedema and surface-triggered thrombosis, and for developing treatments for thrombo-inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Section: A Model For Fxii Activation and Activitymentioning

confidence: 99%

Section: Disease Processes Involving the Kallikrein-kinin Systemmentioning

confidence: 99%

Section: Disease Processes Involving the Kallikrein-kinin Systemmentioning

confidence: 99%

See 2 more Smart Citations

Factor XII Structure–Function Relationships

Shamanaev

Litvak

Ivanov

et al. 2023

Semin Thromb Hemost

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show abstract

“…Coen Maas, from the University Medical Center Utrecht, focused on the mechanism of internal regulation of FXII to prevent premature activation [2]. FXII has a closed conformation to maintain zymogen quiescence and prevent unprovoked BK formation.…”

Section: Day 1 Of Conference: Kks Biologymentioning

confidence: 99%