Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Blood coagulation factor XIII: structure and function.

Blood coagulation factor XIII (FXIII) is a protransglutaminase that becomes activated by the concerted action of thrombin and Ca2+ in the final stage of the clotting cascade. In addition to plasma, FXIII also occurs in platelets, monocytes, and monocyte-derived macrophages. While the plasma factor is a heterotetramer consisting of paired A and B subunits (A2B2), its cellular counterpart lacks the B subunits and is a homodimer of potentially active A subunits (A2). The gene coding for the A and B subunits has been localized to chromosomes 6p24–25 and 1q31–32.1, respectively. The genomic as well as the primary protein structure of both subunits has been established, and most recently the three-dimensional structure of recombinant cellular FXIII has also been revealed. Monocytes/macrophages synthesize their own FXIII, and very likely FXIII in platelets is synthesized by the megakaryocytes. Cells of bone marrow origin seem to be the primary site for the synthesis of subunit A in plasma FXIII, but hepa...

Novel Aspects of Blood Coagulation Factor XIII. I. Structure, Distribution, Activation, and Function

Factor XIII: Inherited and acquired deficiency

Factor XIII is a plasma transglutaminase. Transglutaminases are at least 8 enzymes which cross-link a number of proteins. This type of reaction not only enhances the original functions of substrate proteins, but also adds new functions to them. Factor XIII in plasma is a tetramer (A2B2 ), and the A subunit contains the active site. Although transglutaminases are homologous, the nucleotide sequences in their 5’-flanking region differ significantly. Accordingly, transcription factors play a major role in the cell type-specific expression of each transglutaminase. A variety of missense and nonsense mutations, and deletions/ insertions with or without out-of-frame shift/premature termination and splicing abnormalities have been identified in the genes for A and B subunits in factor XIII deficiency. In some cases, the mRNA level of the A or B subunit was severely reduced. Molecular and cellular bases have also been explored by expression experiments and by molecular modeling. In most cases, impaired folding and/or conformational change of the mutant A or B subunit leads to both intra- and extra-cellular instability, which is responsible for factor XIII deficiency.

Physiopathology and regulation of factor XIII.

We have performed linkage analysis to determine the genetic relationship between the loci coding for coagulation factor XIII B (F13B) and the regulator of complement activation (RCA) gene cluster, comprised of the loci encoding C3b/C4b-receptor (CR1), C3d/Epstein-Barr virus-receptor (CR2), decay accelerating factor (DAF), C4b-binding protein (C4BP), and factor H (HF), as the products of these six loci show structural similarities. Here we report that the human F13B gene is also a member of RCA gene cluster and that it maps in close proximity to the gene encoding complement factor H. Coagulation factor XIII is a tetrameric complex composed of two A and two B polypeptides held together by noncovalent bonds (Schwartz et al. 1973, Chung et al. 1974). Factor XIII is activated by the serine protease thrombin which cleaves a 36 amino acid (aa) peptide from the amino terminus of the catalytic A subunit. In the presence of Ca 2+, the activated A' subunit is released from the B subunit and acquires the transglutaminase enzymatic activity which is responsible for the cross-linking of the fibrin monomers (reviewed in Folk and Finlayson 1977, Lorand et al. 1980). The precise function of the B subunit is not completely understood, but it is thought to protect or stabilize the A subunit, regulating the activation of the zymogen (Cooke 1974). The F13B locus displays a genetic polymorphism (Board 1980), and several phenotypic variants have been characterized by isoelectric focusing (IEF) (Dykes and Polesky 1987). Factor XIII B is structurally related to the members of the so-called superfamily of C3b/C4b binding proteins. These proteins have a structural organization based on the presence of internal repeat units of 60 aa which share a framework of highly conserved residues (reviewed in Reid et al. 1986). Factor XIII B is composed of ten of these repeats which represent the amino terminal 98 % of

Javier Rey-Campos

Papers

Coagulation factor XIII B subunit is encoded by a gene linked to the regulator of complement activation (RCA) gene cluster in man

Complement Activation) Gene Cluster in Humans