Complement factor I
Encyclopedia
Complement factor I, also known as C3B/C4B inactivator, is a protein
that in humans is encoded by the CFI gene
.
Complement Factor I (fI) is a protein of the complement system
, first isolated in 1966 in guinea pig
serum
that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.
(C3) in plasma, due to unregulated activation of the complement alternative pathway, and it has been associated with recurrent bacterial infections in children; more recently, mutations in the Factor I gene have been shown to be implicated in development of Haemolytic Uremic Syndrome
, a renal disease also caused by unregulated complement activation.
for Factor I in humans is located on chromosome 4. Factor I is synthesised mostly in the liver, and is initially secreted as a single 88 kDalton gene product; this precursor protein
is then cleaved by furin
to yield the mature fI protein, which is a disulfide-linked
dimer
of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton). Only the mature protein is active.
-linked glycans
, on three distinct glycosylation
sites each.
The fI heavy chain has four domains: a FIMAC domain, a Scavenger Receptor Cysteine Rich (SRCR) domain and two LDL-receptor Class A domains; the heavy chain plays an inhibitory role in maintaining the enzyme inactive until it meets the complex formed by the substrate
(either C3b or C4b) and a cofactor protein (Factor H
, CR1, MCP or C4BP). Upon binding of the enzyme to the substrate:cofactor complex, the heavy:light chain interface is disrupted, and the enzyme activated by allostery . The LDL-receptor domains contain one Calcium-binding site each.
The fI light chain is the serine protease
domain containing the catalytic triad
responsible for specific cleavage of C3b and C4b.
Conventional protease inhibitors do not completely inactivate Factor I but they can do so if the enzyme is pre-incubated with its substrate: this supports the proposed rearrangement of the molecule upon binding to the substrate.
Genetic polymorphism in Factor I has been observed and recently explained in terms of variants R201S, R406H, R502L.
Crystal structure
the crystal structure of human Factor I has been deposited as .
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the CFI gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Complement Factor I (fI) is a protein of the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
, first isolated in 1966 in guinea pig
Guinea pig
The guinea pig , also called the cavy, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family, nor are they from Guinea...
serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.
Pathology
Factor I deficiency in turn leads to low levels of complement component 3C3 (complement)
Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.-Function:...
(C3) in plasma, due to unregulated activation of the complement alternative pathway, and it has been associated with recurrent bacterial infections in children; more recently, mutations in the Factor I gene have been shown to be implicated in development of Haemolytic Uremic Syndrome
Hemolytic-uremic syndrome
Hemolytic-uremic syndrome , abbreviated HUS, is a disease characterized by hemolytic anemia, acute renal failure and a low platelet count . It predominantly, but not exclusively, affects children. Most cases are preceded by an episode of diarrhea caused by E. coli O157:H7, which is acquired as a...
, a renal disease also caused by unregulated complement activation.
Synthesis
The geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for Factor I in humans is located on chromosome 4. Factor I is synthesised mostly in the liver, and is initially secreted as a single 88 kDalton gene product; this precursor protein
Protein precursor
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein that can be turned into an active form by posttranslational modification. The name of the precursor for a protein is often prefixed by pro...
is then cleaved by furin
Furin
Furin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin...
to yield the mature fI protein, which is a disulfide-linked
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton). Only the mature protein is active.
Structure
Both heavy and light chains bear AsnAsparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
-linked glycans
Glycans
The term glycan refers to a polysaccharide or oligosaccharide. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan composed of beta-1,4-linked D-glucose, and chitin is a glycan composed of beta-1,4-linked N-acetyl-D-glucosamine...
, on three distinct glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
sites each.
The fI heavy chain has four domains: a FIMAC domain, a Scavenger Receptor Cysteine Rich (SRCR) domain and two LDL-receptor Class A domains; the heavy chain plays an inhibitory role in maintaining the enzyme inactive until it meets the complex formed by the substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
(either C3b or C4b) and a cofactor protein (Factor H
Factor H
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large , soluble glycoprotein that circulates in human plasma...
, CR1, MCP or C4BP). Upon binding of the enzyme to the substrate:cofactor complex, the heavy:light chain interface is disrupted, and the enzyme activated by allostery . The LDL-receptor domains contain one Calcium-binding site each.
The fI light chain is the serine protease
Serine protease
Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
domain containing the catalytic triad
Catalytic triad
A catalytic triad refers to the three amino acid residues found inside the active site of certain protease enzymes: serine , aspartate , and histidine . They work together to break peptide bonds on polypeptides. In general terms, catalytic triad can refer to any set of three residues that function...
responsible for specific cleavage of C3b and C4b.
Conventional protease inhibitors do not completely inactivate Factor I but they can do so if the enzyme is pre-incubated with its substrate: this supports the proposed rearrangement of the molecule upon binding to the substrate.
Genetic polymorphism in Factor I has been observed and recently explained in terms of variants R201S, R406H, R502L.
Crystal structure
Crystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...
the crystal structure of human Factor I has been deposited as .
External links
- GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome
- OMIM entries on Atypical Hemolytic-Uremic Syndrome
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: S01.199