BCR (gene)
Protein domain
From Wikipedia, the free encyclopedia
The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL fusion protein, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.
Structure
Native protein
From the N-terminal to the C-terminal, BCR has a largely disordered kinase region (1-426), a DH domain (498-691), a PH domain (708-866), a C2 domain (893-1020), and a Rho-GAP (1054-1248) domain. The Protein Data Bank includes experimental structures for residues 1–72 (oncoprotein oligomerisation domain, see below), 1277–1271 (a C-terminal tail), 487-702 (DH), and 704-893 (PH).[5]
Oncoprotein
In the BCR-ABL oncoprotein, the N-terminal part of BCR is fused to the C-termianl part of ABL. The approximately 75 residues on the N-terminus functions as an oligomerisation domain essential for the oncogenicity of the BCR-ABL fusion protein. This 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.[6] 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.[7]
The kinase also includes a region that binds the ABL SH2 domain.[5]
Function
Although the BCR-ABL fusion protein has been much studied, the function of the normal BCR gene product is still not clear. The protein has serine/threonine kinase activity and is a guanine nucleotide exchange factor for the Rho family of GTPases including RhoA.[8][9]
BCR is a paralog of ABR, RhoGEF and GTPase activating protein. Both are GTPase-activating proteins selective for Rac. Despite their "GTPase-activating" domain they actually reduce the activity of Rac.[10] They keep mature innate immune system cells from becoming overactive.[11]
BCR knockout mice are viable, fertile, and free of obvious behavioral or physical abnormalities. They are however much more sensitive to lipopolysaccharide in blood, reacting with neutrophilia and septic shock. Their neutrophils are more active than those of normal mice.[12] BCR knockout also disrupts gut movement and brain development in mice.[13]
Interactions
Clinical significance
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.[35]