Factor XIII or fibrin stabilizing factor is a zymogen found in blood of humans and some other animals. It is activated by thrombin to factor XIIIa. Factor XIIIa is an enzyme of the blood coagulation system that crosslinks

fibrin Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...

. Deficiency of XIII worsens clot stability and increases bleeding tendency. Human XIII is a heterotetramer. It consists of 2 enzymatic A peptides and 2 non-enzymatic B peptides. XIIIa is a dimer of activated A peptides.

Function

Within blood, thrombins cleave fibrinogens to fibrins during coagulation and a fibrin-based blood clot forms. Factor XIII is a transglutaminase that circulates in human blood as a heterotetramer of two A and two B subunits. Factor XIII binds to the clot via their B units. In the presence of fibrins, thrombin efficiently cleaves the R37– G38

peptide bond In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...

of each A unit within a XIII tetramer. A units release their

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

activation peptides. Both of the non- covalently bound B units are now able to dissociate from the tetramer with the help of calcium ions (Ca²⁺) in the blood; these ions also activate the remaining dimer of two A units via a conformational change. Factor XIIIa (dimer of two active A units) crosslinks fibrins within the clot by forming isopeptide bonds between various glutamines and

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

s of the fibrins. These bonds make the clot physically more durable and protect it from premature enzymatic degradation ( fibrinolysis). In humans, plasmin, antithrombin and TFPI are the most relevant proteolytic inhibitors of the active factor XIIIa. α2-macroglobulin is a significant non-proteolytic inhibitor. Factor XIII activation via thrombin.svg, Activation peptides (pink) of A units are removed by thrombin (IIa) in the presence of fibrin. B units (gray) are released with the help of calcium and A unit dimer is activated (XIIIa forms). Stabilisation de la fibrine par le factor XIII.png, XIIIa crosslinks fibrin (simplified picture)

Genetics

Human factor XIII consist of A and B subunits. A subunit gene is '' F13A1''. It is on the

chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total ...

at the position 6p24–25. It spans over 160 kbp, has 14

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

s and 15

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s. Its mRNA is 3.9 kbp. It has a

5' UTR The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of ...

of 84 bp and a

3' UTR In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...

of 1.6 kbp. ''F13A1'' exon(s) *1 code 5' UTR *2 code activation peptide *2–4 code

β-sandwich Beta-sandwich, β-sandwich domains consisting of 80 to 350 amino acids occur commonly in proteins. They are characterized by two opposing antiparallel beta sheets (β-sheets). The number of strands found in such domains may differ from one protein ...

*4–12 code

catalytic domain In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate ( binding si ...

*12–13 code

β-barrel In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...

1 *13–15 code β-barrel 2 B subunit gene is '' F13B''. It is on the chromosome 1 at the position 1q31–32.1. It spans 28 kpb, has 11 introns and 12 exons. Its mRNA is 2.2 kbp. Exon 1 codes 5' UTR. Exons 2–12 code the 10 different

sushi domain Sushi domain is an evolutionarily conserved protein domain. It is also known as Complement control protein (CCP) modules or short consensus repeats (SCR). The name derives from the visual similarity of the domain to nigiri sushi when the prim ...

Structure

Factor XIII of human blood is a heterotetramer of two A and two B linear polypeptides or "units". A units are potentially catalytic; B units are not. A units form a dimeric center. Non- covalently bound B units form a ring-like structure around the center. B units are removed when XIII is activated to XIIIa. Dimers containing only A units also occur within cells such as platelets. Large quantities of singular B units (monomers) also occur within blood. These dimers and monomers are not known to participate in coagulation, whereas the tetramers do. A units have a mass of about 83 kDa, 731 amino acid residues, 5 protein domains (listed from the

to C-terminal, residue numbers are in brackets): *activation peptide (1–37) *

(38–184) *

(185–515), in which the residues C314, H373, D396 and W279 partake in catalysis *

1 (516–628) *β-barrel 2 (629–731) B units are

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

s. Each has a mass of about 80 kDa (8.5% of the mass is from carbohydrates), 641 residues and 10

s. Each domain has about 60 residues and 2 internal disulfide bonds.

Physiology

A subunits of human factor XIII are made primarily by platelets and other cells of

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

origin. B subunits are secreted into blood by hepatocytes. A and B units combine within blood to form heterotetramers of two A units and two B units. Blood plasma concentration of the heterotetramers is 14–48 mg/L and half-life is 9–14 days. A clot that has not been stabilized by FXIIIa is soluble in 5 mol/L urea, while a stabilized clot is resistant to this phenomenon.

Factor XIII deficiency

Deficiency of Factor XIII (FXIIID), while generally rare, does occur, with Iran having the highest global incidence of the disorder with 473 cases. The city of

Khash Khash may refer to: *Khash (dish), South Caucasian dish *Khash Rod District, a district in Nimruz Province, Afghanistan **Khash, Nimruz, capital of Khash Rod District, Afghanistan * Khash District, a district in Badakhshan Province, Afghanistan *K ...

, located in Sistan and Balochistan provinces, has the highest incidence in Iran, with a high rate of consanguineous marriage.

Diagnostic use

Factor XIII levels are not measured routinely, but may be considered in patients with an unexplained bleeding tendency. As the enzyme is quite specific for monocytes and

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s, determination of the presence of factor XIII may be used to identify and classify malignant diseases involving these cells.

Discovery

Factor XIII Deficiency is also known as Laki–Lorand factor, after Kalman Laki and

Laszlo Lorand Laszlo Lorand (23 March 1923 – 6 December 2018) was a Hungarian-American biochemist who studied clotting of blood and other bodily fluids. A professor emeritus in cell and molecular biology at the Feinberg School of Medicine, Lorand was a longt ...

, the scientists who first proposed its existence in 1948. A 2005 conference recommended standardization of nomenclature.

References

External links

Factor XIII deficiency at hemophilia.org
* {{Authority control Coagulation system EC 2.3.2 Zymogens