Activin A receptor, type I (ACVR1) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

which in humans is encoded by the ''ACVR1''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

; also known as ALK-2 (activin receptor-like kinase-2). ACVR1 has been linked to the 2q23-24 region of the genome. This protein is important in the

bone morphogenic protein Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pi ...

(BMP) pathway which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to

fibrodysplasia ossificans progressiva Fibrodysplasia ossificans progressiva (; FOP; also called Münchmeyer disease and formerly called myositis ossificans progressiva or Stoneman disease) is an extremely rare connective tissue disease in which fibrous connective tissue such as mu ...

, a disease characterized by the formation of heterotopic bone throughout the body. It is a bone morphogenetic protein receptor, type 1.

Function

Activin Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual ...

s are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (

TGF beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all

transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...

s, composed of a ligand-binding

extracellular domain An ectodomain is the Protein domain, domain of a Cell membrane, membrane protein that extends into the extracellular space (the space outside a cell (biology), cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces ...

with cysteine-rich region, a

transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...

, and a cytoplasmic domain with predicted

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...

specificity. Type I receptors are essential for signaling; and type II receptors are required for binding

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

s and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors.

Signaling

ACVR1 transduces signals of BMPs. BMPs bind either

ACVR2A Activin receptor type-2A is a protein that in humans is encoded by the ''ACVR2A'' gene. ACVR2A is an activin type 2 receptor. Function This gene encodes activin A type II receptor. Activins are dimeric growth and differentiation factors which ...

ACVR2B Activin receptor type-2B is a protein that in humans is encoded by the ''ACVR2B'' gene. ACVR2B is an activin type 2 receptor. Function Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-bet ...

or a

BMPR2 Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase. It binds Bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signalling. BMPs are involved in a ho ...

and then form a complex with ACVR1. These go on to recruit the

R-SMAD R-SMADs are receptor-regulated SMADs. SMADs are transcription factors that transduce extracellular TGF-β superfamily ligand signaling from cell membrane bound TGF-β receptors into the nucleus where they activate transcription TGF-β target ge ...

s SMAD1, SMAD2, SMAD3 or

SMAD6 SMAD family member 6, also known as SMAD6, is a protein that in humans is encoded by the ''SMAD6'' gene. SMAD6 is a protein that, as its name describes, is a homolog of the Drosophila gene "mothers against decapentaplegic". It belongs to the SM ...

Clinical significance

Gain-of-function mutations in the gene ACVR1/ALK2 is responsible for the genetic disease

. The typical FOP patient has the amino acid arginine substituted for the amino acid histidine at position 206 in this protein. This causes a change in the critical glycine-serine activation domain of the protein which will cause the protein to bind its inhibitory ligand (FKBP12) less tightly, and thus over-activate the BMP/SMAD pathway. The result of this over-activation is that

endothelial cell The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...

s transform to

mesenchymal stem cell Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cel ...

s and then to bone. Atypical mutations involving other residues work similarly - causing the protein to be stuck in its active conformation despite no BMP being present. Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma (DIPG).

References

External links

* * {{DEFAULTSORT:Acvr1 GS domain TS domain S/T domain Human proteins EC 2.7.11