The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''BCR''

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 ...

. ''BCR'' is one of the two genes in the ''BCR-ABL'' fusion protein, which is associated with the

Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is an abnormal version of chromosome 22 where a part of the ''ABL (gene), Abelson murine leukemia'' 1 (''ABL1'') gene on chromosome 9 breaks off and attaches to the ''BCR (gene), break ...

. Two transcript variants encoding different isoforms have been found for this gene.

Function

Although the BCR- ABL

fusion protein Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this '' fusion gene'' ...

has been much studied, the function of the normal BCR gene product is still not clear. The protein has

serine/threonine kinase A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prote ...

activity and is a

guanine nucleotide exchange factor Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structu ...

for the

Rho family of GTPases The Rho family of GTPases is a family of small (~21 kDa) signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found ...

including

RhoA Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...

Clinical significance

A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with

chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumula ...

. The chromosome 22 breakpoint for this translocation is located within the ''BCR'' gene. The translocation produces a fusion protein that is encoded by sequence from both ''BCR'' and ''ABL'', the gene at the chromosome 9 breakpoint.

Structure

Schematic of the Philadelphia Chromosome

The BCR-ABL oncoprotein oligomerisation domain found at the

N-terminus 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 amin ...

of BCR is essential for the

oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

ity of the BCR-ABL fusion protein. The BCR-ABL oncoprotein oligomerisation domain consists of a short N-terminal

helix A helix (; ) is a shape like a cylindrical coil spring or the thread of a machine screw. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is for ...

(alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two

helices A helix (; ) is a shape like a cylindrical coil spring or the thread of a machine screw. It is a type of smoothness (mathematics), smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as ...

to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel

coiled coil A coiled coil is a structural motif in proteins in which two to seven alpha-helices are coiled together like the strands of a rope. ( Dimers and trimers are the most common types.) They have been found in roughly 5-10% of proteins and have a ...

between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second

monomer A monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called polymerization. Classification Chemis ...

. Two dimers then associate into a

tetramer A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula ...

. Structure-based engineering starting from the antiparallel coiled coil domain of the BCR-ABL oncoprotein (BCR30-65) resulted in a new pH-sensitive homodimeric antiparallel coiled coil.

Interactions

The BCR protein has been shown to interact with: *

Abl gene Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ''ABL1'' gene (previous symbol ''ABL'') located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammali ...

, *

CD117 Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 ( cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding d ...

, *

CRKL Crk-like protein is a protein that in humans is encoded by the CRKL gene. Function v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling pat ...

* FES, *

Grb2 Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/ cell communication. In humans, the GRB2 protein is encoded by the ''GRB2'' gene. The protein encoded by this gene binds recepto ...

, *

GRB10 Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the ''GRB10'' gene. Function The product of this gene belongs to a small family of Signal transducing adapto ...

, * HCK, *

MLLT4 Afadin is a protein that in humans is encoded by the ''AFDN'' gene. Function Afadin is a Ras (see HRAS; MIM 190020) target that regulates cell–cell adhesions downstream of Ras activation. It is fused with MLL (MIM 159555) in leukemias caused ...

, * PXN, * PIK3CG, *

PTPN6 Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene. Function The protein encoded by this gene is a member ...

, *

PTPRT Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the ''PTPRT'' gene. PTPRT is also known as PTPrho, PTPρ and human accelerated region 9. The human accelerated regions are 49 regions of the human genome tha ...

(PTPrho) *

SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the ''SOS1'' gene. Function SOS1 is a guanine nucleotide exchange factor (GEF) which interacts with Ras protein, Ras proteins to phosphorylate GDP into GTP, or from an inacti ...

, and * XPB.

References

External links

* * * {{InterPro content, IPR015123 Genes on human chromosome 22 Protein kinases