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8  structures 8  species 0  interactions 32  sequences 7  architectures

Family: Bcr-Abl_Oligo (PF09036)

Summary: Bcr-Abl oncoprotein oligomerisation domain

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This is the Wikipedia entry entitled "BCR gene". More...

BCR gene Edit Wikipedia article

Breakpoint cluster region

PDB rendering based on 1k1f.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BCR; ALL; BCR1; CML; D22S11; D22S662; PHL
External IDs OMIM: 151410 MGI: 88141 HomoloGene: 3192 GeneCards: BCR Gene
EC number 2.7.11.1
Orthologs
Species Human Mouse
Entrez 613 110279
Ensembl ENSG00000186716 ENSMUSG00000009681
UniProt P11274 Q6PAJ1
RefSeq (mRNA) NM_004327.3 NM_001081412.2
RefSeq (protein) NP_004318.3 NP_001074881.1
Location (UCSC) Chr 22:
23.52 – 23.66 Mb		 Chr 10:
74.52 – 74.65 Mb
PubMed search [1] [2]
This box:
Bcr-Abl oncoprotein oligomerisation domain
PDB 1k1f EBI.jpg
structure of the bcr-abl oncoprotein oligomerization domain
Identifiers
Symbol Bcr-Abl_Oligo
Pfam PF09036
InterPro IPR015123

The BCR gene (breakpoint cluster region) is one of the two genes in the bcr-abl complex, which is associated with the Philadelphia chromosome.

Contents

[edit] Pathology

A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. 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. Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The protein has serine/threonine kinase activity and is a GTPase-activating protein for p21rac. Two transcript variants encoding different isoforms have been found for this gene.[1]

The Bcr-Abl oncoprotein oligomerisation domain found at the N-terminus of BCR is essential for the oncogenicity of the BCR-ABL fusion protein. The Bcr-Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (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 to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil 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. Two dimers then associate into a tetramer.[2]

[edit] Interactions

BCR gene has been shown to interact with PTPN6,[3] XPB,[4] Feline sarcoma oncogene,[5][6] GRB10,[7] CD117,[8] Grb2,[6][7][9][10][11][12] MLLT4,[13] Abl gene,[11][14][15] HCK,[16][17] SOS1,[6][11] PIK3CG,[7][18][19] CRKL[7][10][20][21] and Paxillin.[18][22]

[edit] See also

[edit] References

  1. ^ "Entrez Gene: BCR breakpoint cluster region". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=613. 
  2. ^ Zhao X, Ghaffari S, Lodish H, Malashkevich VN, Kim PS (February 2002). "Structure of the Bcr-Abl oncoprotein oligomerization domain". Nat. Struct. Biol. 9 (2): 117–20. doi:10.1038/nsb747. PMID 11780146. 
  3. ^ Liedtke, M; Pandey P, Kumar S, Kharbanda S, Kufe D (October 1998). "Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase". Oncogene (ENGLAND) 17 (15): 1889–92. doi:10.1038/sj.onc.1202117. ISSN 0950-9232. PMID 9788431. 
  4. ^ Takeda, N; Shibuya M, Maru Y (January 1999). "The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 96 (1): 203–7. doi:10.1073/pnas.96.1.203. ISSN 0027-8424. PMC 15117. PMID 9874796. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=15117. 
  5. ^ Lionberger, J M; Smithgall T E (February 2000). "The c-Fes protein-tyrosine kinase suppresses cytokine-independent outgrowth of myeloid leukemia cells induced by Bcr-Abl". Cancer Res. (UNITED STATES) 60 (4): 1097–103. ISSN 0008-5472. PMID 10706130. 
  6. ^ a b c Maru, Y; Peters K L, Afar D E, Shibuya M, Witte O N, Smithgall T E (February 1995). "Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS". Mol. Cell. Biol. (UNITED STATES) 15 (2): 835–42. ISSN 0270-7306. PMC 231961. PMID 7529874. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=231961. 
  7. ^ a b c d Bai, R Y; Jahn T, Schrem S, Munzert G, Weidner K M, Wang J Y, Duyster J (August 1998). "The SH2-containing adapter protein GRB10 interacts with BCR-ABL". Oncogene (ENGLAND) 17 (8): 941–8. doi:10.1038/sj.onc.1202024. ISSN 0950-9232. PMID 9747873. 
  8. ^ Hallek, M; Danhauser-Riedl S, Herbst R, Warmuth M, Winkler A, Kolb H J, Druker B, Griffin J D, Emmerich B, Ullrich A (July 1996). "Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells". Br. J. Haematol. (ENGLAND) 94 (1): 5–16. doi:10.1046/j.1365-2141.1996.6102053.x. ISSN 0007-1048. PMID 8757502. 
  9. ^ Million, R P; Van Etten R A (July 2000). "The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase". Blood (UNITED STATES) 96 (2): 664–70. ISSN 0006-4971. PMID 10887132. 
  10. ^ a b Million, Ryan P; Harakawa Nari, Roumiantsev Sergei, Varticovski Lyuba, Van Etten Richard A (June 2004). "A Direct Binding Site for Grb2 Contributes to Transformation and Leukemogenesis by the Tel-Abl (ETV6-Abl) Tyrosine Kinase". Mol. Cell. Biol. (United States) 24 (11): 4685–95. doi:10.1128/MCB.24.11.4685-4695.2004. ISSN 0270-7306. PMC 416425. PMID 15143164. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=416425. 
  11. ^ a b c Puil, L; Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci P G, Arlinghaus R, Pawson T (February 1994). "Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway". EMBO J. (ENGLAND) 13 (4): 764–73. ISSN 0261-4189. PMC 394874. PMID 8112292. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=394874. 
  12. ^ Ma, G; Lu D, Wu Y, Liu J, Arlinghaus R B (May. 1997). "Bcr phosphorylated on tyrosine 177 binds Grb2". Oncogene (ENGLAND) 14 (19): 2367–72. doi:10.1038/sj.onc.1201053. ISSN 0950-9232. PMID 9178913. 
  13. ^ Radziwill, G; Erdmann R A, Margelisch U, Moelling K (July 2003). "The Bcr Kinase Downregulates Ras Signaling by Phosphorylating AF-6 and Binding to Its PDZ Domain". Mol. Cell. Biol. (United States) 23 (13): 4663–72. doi:10.1128/MCB.23.13.4663-4672.2003. ISSN 0270-7306. PMC 164848. PMID 12808105. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=164848. 
  14. ^ Ling, Xiaoyang; Ma Guozhen, Sun Tong, Liu Jiaxin, Arlinghaus Ralph B (January 2003). "Bcr and Abl interaction: oncogenic activation of c-Abl by sequestering Bcr". Cancer Res. (United States) 63 (2): 298–303. ISSN 0008-5472. PMID 12543778. 
  15. ^ Pendergast, A M; Muller A J, Havlik M H, Maru Y, Witte O N (July 1991). "BCR sequences essential for transformation by the BCR-ABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner". Cell (UNITED STATES) 66 (1): 161–71. doi:10.1016/0092-8674(91)90148-R. ISSN 0092-8674. PMID 1712671. 
  16. ^ Stanglmaier, M; Warmuth M, Kleinlein I, Reis S, Hallek M (February 2003). "The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains". Leukemia (England) 17 (2): 283–9. doi:10.1038/sj.leu.2402778. ISSN 0887-6924. PMID 12592324. 
  17. ^ Lionberger, J M; Wilson M B, Smithgall T E (June 2000). "Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck". J. Biol. Chem. (UNITED STATES) 275 (24): 18581–5. doi:10.1074/jbc.C000126200. ISSN 0021-9258. PMID 10849448. 
  18. ^ a b Salgia, R; Sattler M, Pisick E, Li J L, Griffin J D (February 1996). "p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl". Exp. Hematol. (UNITED STATES) 24 (2): 310–3. ISSN 0301-472X. PMID 8641358. 
  19. ^ Skorski, T; Kanakaraj P, Nieborowska-Skorska M, Ratajczak M Z, Wen S C, Zon G, Gewirtz A M, Perussia B, Calabretta B (July 1995). "Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells". Blood (UNITED STATES) 86 (2): 726–36. ISSN 0006-4971. PMID 7606002. 
  20. ^ Heaney, C; Kolibaba K, Bhat A, Oda T, Ohno S, Fanning S, Druker B J (January 1997). "Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation". Blood (UNITED STATES) 89 (1): 297–306. ISSN 0006-4971. PMID 8978305. 
  21. ^ Kolibaba, K S; Bhat A, Heaney C, Oda T, Druker B J (March 1999). "CRKL binding to BCR-ABL and BCR-ABL transformation". Leuk. Lymphoma (SWITZERLAND) 33 (1–2): 119–26. doi:10.3109/10428199909093732. ISSN 1042-8194. PMID 10194128. 
  22. ^ Salgia, R; Li J L, Lo S H, Brunkhorst B, Kansas G S, Sobhany E S, Sun Y, Pisick E, Hallek M, Ernst T (March 1995). "Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL". J. Biol. Chem. (UNITED STATES) 270 (10): 5039–47. doi:10.1074/jbc.270.10.5039. ISSN 0021-9258. PMID 7534286. 

[edit] External links

[edit] Further reading

  • Wang L, Seale J, Woodcock BE, Clark RE (2002). "e19a2-positive chronic myeloid leukaemia with BCR exon e16-deleted transcripts". Leukemia 16 (8): 1562–3. doi:10.1038/sj.leu.2402600. PMID 12145699. 


This article incorporates text from the public domain Pfam and InterPro IPR015123


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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Bcr-Abl oncoprotein oligomerisation domain

The Bcr-Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (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 to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil 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. Two dimers then associate into a tetramer. The oligomerisation domain is essential for the oncogenicity of the Bcr-Abl protein [1].

Literature references

  1. Zhao X, Ghaffari S, Lodish H, Malashkevich VN, Kim PS; , Nat Struct Biol. 2002;9:117-120.: Structure of the Bcr-Abl oncoprotein oligomerization domain. PUBMED:11780146

External database links

PANDIT: PF09036
Pseudofam: PF09036
SYSTERS: Bcr-Abl_Oligo

This tab holds annotation information from the InterPro database.

InterPro entry IPR015123

This entry represents the oligomerisation domain of the breakpoint cluster region oncoprotein Bcr, and the Bcr/Abl (Abelson-leukemia-virus) fusion protein created by a reciprocal (9;22) fusion [PUBMED:17090304]. Brc displays serine/threonine protein kinase activity (EC), acting as a GTPase-activating protein for RAC1 and CDC42. Brc promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them [PUBMED:15302586]. The Bcr/Abl fusion protein loses some of the regulatory function of Bcr with regards to small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells [PUBMED:17090304].

The Bcr, Bcr/Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (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 to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil 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. Two dimers then associate into a tetramer. The oligomerisation domain is essential for the oncogenicity of the Bcr-Abl protein [PUBMED:11780146].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Molecular function protein serine/threonine kinase activity (GO:0004674)
GTPase activator activity (GO:0005096)
Biological process signal transduction (GO:0007165)
protein phosphorylation (GO:0006468)

Domain organisation

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Alignments

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Curation and family details

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Seed source: pdb_1k1f
Previous IDs: none
Type: Domain
Author: Mistry J, Sammut SJ
Number in seed: 4
Number in full: 32
Average length of the domain: 75.10 aa
Average identity of full alignment: 85 %
Average coverage of the sequence by the domain: 8.57 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 15929002 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.9 20.9
Trusted cut-off 21.1 32.0
Noise cut-off 20.4 19.0
Model length: 79
Family (HMM) version: 5
Download: download the raw HMM for this family

Species distribution

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Viroids Viroids Unclassified sequence Unclassified sequence

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Bcr-Abl_Oligo domain has been found. There are 8 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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