The kinase pathways, in essence, induce phosphorylation of a single residue SER133 (Salks Institute, Undated) on CREB to activate it. There is evidence of four such kinase pathways - cAMP-dependent protein kinase, multiple mitogen-activated protein kinases (MAPKs), ribosome S6 kinase and - and calmodulin-dependent kinases (CAMKs) (Euskirchen, G., et al, 2004). The phosphorylated CREB attracts coactivator CREB binding protein (CBP or CREBBP ) which allows the activated phosphorylated CREB to bind to cAMP-responsive element (CRE) sequences on DNA to initiate gene expression (Thiel, G., et al, 2005). CBP coactivator work is often copied by its paralog p300, a highly related transcriptional coactivator protein targeted by the adenoviral oncoprotein E1A (Brody, T.B., 1996). This is still not a very clear process as much has yet to be known about the mechanism by which CBP binds to the phosphorylated CREB and subsequently promotes gene transcription. For gene transcription to take place a polymerase complex must be recruited, it must then be subsequently isomerized and cleared to transcribe the target gene (Kim, J., et al, 2000). There is evidence that the phsophorylated CREB, after binding with CBP, also recruits a RNA(2) polymerase complex to initiate transcription on CRE elements on target genes in various cells and tissues (Kim, J., et al, 2000). There is much that has been cleared in this direction by the research efforts of Kim et al, 2000, yet more has to be done before any definite conclusions can be reached. The paper now focuses on the molecular and genetic identity of CBP so that the next section on possible mutations on the protein can be better understood.
Nevertheless, it is noted here that CREB activity is triggered off by diverse factors such as growth factors, hormones, neurotransmitters, ion fluxes and stress signals (Euskirchen, G., et al, 2004), all of which help recruit the protein. CBP action is initiated through heterodimerization of basic leucine zipper (bZIP) domains (Euskirchen, G., et al, 2004). Its action via gene transcription is also very diverse and the number of genes it helps express is also >100. Thus, mutations in CREBBP or CREB binding protein have numerous implications.
The CREB Binding Protein (CBP or CREBBP)
CBP is encoded in DNA sequences on human chromosome 16 at 16p13.3 (CREBBP, GeneCard, 2006). Gene location is from GC16M003716 to GC16M003870. The sequence starts at 3,716,568 bp from p terminal and ends at 3,870,723 bp from p terminal making up a sequence of size 154,155 bases with a minus strand orientation (CREBBP, GeneCard, 2006). The human CBP is made up of 2442 amino acid sequences and is 265337 Daltons in molecular weight (CREBBP, GeneCard, 2006). A rough domain count of the protein sequences is available for isoform 'a'. These are as per Table 1 and Diagram 1, Appendix, sourced from Giles et al, 1997, Fig. 3 and 4 respectively. As can be observed from both the table and the diagram, there are 11 distinct domains. This is not exhaustive as there are many regions on the total CREBBP (human) DNA sequence that have not been mapped according to function