Vitronectin (VTN or VN) is a
glycoprotein of the
hemopexin family which is synthesized and excreted by the liver, and abundantly found in serum, the
extracellular matrix and
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
. In humans it is encoded by the ''VTN''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Vitronectin binds to
integrin alpha-V beta-3 and thus promotes
cell adhesion
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as Cell_junction, cell junc ...
and spreading. It also inhibits the membrane-damaging effect of the terminal cytolytic
complement pathway and binds to several
serpins (serine protease inhibitors). It is a secreted protein and exists in either a single chain form or a clipped, two chain form held together by a disulfide bond.
Vitronectin has been speculated to be involved in
hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. Hemostasis involves three ...
and
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
malignancy.
Structure
Vitronectin is a 75 kDa glycoprotein, consisting of 478
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
residues. About one-third of the protein's
molecular mass
The molecular mass () is the mass of a given molecule, often expressed in units of daltons (Da). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The derived quan ...
is composed of
carbohydrate
A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...
s. On occasion, the protein is cleaved after
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
379, to produce two-chain vitronectin, where the two parts are linked by a
disulfide bond. No high-resolution structure has been determined experimentally yet,
except for the N-terminal domain.
The protein consists of three
domains:
* The
N-terminal Somatomedin B domain (1-39)
* A central domains with
hemopexin homology (131-342)
* A
C-terminal domain (residues 347-459) also with hemopexin homology.
Several structures has been reported for the Somatomedin B domain. The protein was initially crystallized in complex with one of its physiological binding partners: the
Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor (serpin E1) is a protein that in humans is encoded by the ''SERPINE1'' gene. Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.
...
(PAI-1) and the structure solved for this complex.
Subsequently two groups reported
NMR structures of the domain.
The somatomedin B domain is a close-knit disulfide knot, with 4 disulfide bonds within 35 residues. Different disulfide configurations had been reported for this domain
but this ambiguity has been resolved by the crystal structure.
have been built for the central and C-terminal domains.
Function
The somatomedin B domain of vitronectin binds to
plasminogen activator inhibitor-1
Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor (serpin E1) is a protein that in humans is encoded by the ''SERPINE1'' gene. Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis.
...
(PAI-1), and stabilizes it.
Thus vitronectin serves to regulate proteolysis initiated by
plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin thrombus, clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) i ...
ogen activation. In addition, vitronectin is a component of
platelets and is, thus, involved in hemostasis. Vitronectin contains an RGD (45-47) sequence, which is a binding site for membrane-bound
integrins, e.g., the
vitronectin receptor, which serve to anchor cells to the extracellular matrix. The Somatomedin B domain interacts with the
urokinase receptor
The Urokinase receptor, also known as urokinase plasminogen activator surface receptor (uPAR) or CD87 (Cluster of Differentiation 87), is a protein encoded in humans by the PLAUR gene. It is a multidomain glycoprotein tethered to the cell membr ...
, and this interaction has been implicated in cell migration and signal transduction. High plasma levels of both PAI-1 and the urokinase receptor have been shown to correlate with a negative prognosis for cancer patients. Cell adhesion and migration are directly involved in cancer
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
, which provides a probable mechanistic explanation for this observation.
References
Further reading
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External links
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{{Fibrous proteins
Glycoproteins
Extracellular matrix proteins
Cell adhesion proteins