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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''BCR''
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 ba ...
. ''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 a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
. 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'' r ...
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 accumulat ...
. 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](https://upload.wikimedia.org/wikipedia/commons/c/c6/Schematic_of_the_Philadelphia_Chromosome.svg)
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 ami ...
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 corkscrew or spiral staircase. 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 formed as two intertwined helices, ...
(alpha-1), a flexible
loop
Loop or LOOP may refer to:
Brands and enterprises
* Loop (mobile), a Bulgarian virtual network operator and co-founder of Loop Live
* Loop, clothing, a company founded by Carlos Vasquez in the 1990s and worn by Digable Planets
* Loop Mobile, an ...
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 corkscrew or spiral staircase. 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 formed as two intertwined helices, ...
to assume a parallel orientation. The monomeric
domains associate into a
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ...
through the formation of an
antiparallel coiled coil
A coiled coil is a structural motif in proteins in which 2–7
alpha-helices are coiled together like the strands of a rope. (Dimers and trimers are the most common types.) Many coiled coil-type proteins are involved in important biological fun ...
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
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
Mo ...
. 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 Ti ...
.
Structure-based engineering starting from the antiparallel coiled coil domain of the BCR-ABL oncoprotein (BCR
30-65) resulted in a new pH-sensitive homodimeric antiparallel coiled coil.
Interactions
The BCR protein has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
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 mammalian ...
,
* 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 diff ...
,
* 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 pathw ...
* FES
Fez or Fes (; ar, فاس, fās; zgh, ⴼⵉⵣⴰⵣ, fizaz; french: Fès) is a city in northern inland Morocco and the capital of the Fès-Meknès administrative region. It is the second largest city in Morocco, with a population of 1.11 mi ...
,
* Grb2,
* 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 adaptor proteins that are ...
,
* HCK
Tyrosine-protein kinase HCK is an enzyme that in humans is encoded by the ''HCK'' gene.
Function
The protein encoded by this gene is a protein-tyrosine kinase that is predominantly expressed in hemopoietic cell types, and belongs to the Src f ...
,
* 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
Paxillin is a protein that in humans is encoded by the ''PXN'' gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutation ...
,
* PIK3CG
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform is an enzyme that in humans is encoded by the ''PIK3CG'' gene.
Function
This gene encodes a protein that belongs to the pi3/pi4-kinase family of proteins. The gene p ...
,
* 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 that ...
(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 proteins to phosphorylate GDP into GTP, or from an inactive state to an ...
,[ and
* ]XPB
XPB (xeroderma pigmentosum type B) is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex.
Structure
The 3D-structure of the archaeal homolog of XPB has been solved by X-ray crystallography by Dr. Jo ...
.
See also
* 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 mammalian ...
References
Further reading
*
External links
*
*
*
{{InterPro content, IPR015123
Genes on human chromosome 22
Protein kinases