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Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders.

Valor LM, Viosca J, Lopez-Atalaya JP, Barco A - Curr. Pharm. Des. (2013)

Bottom Line: Among the possible original factors, epigenetic dysregulation has attracted special attention.This review focuses on two highly related epigenetic factors that are directly involved in a number of neurological disorders, the lysine acetyltransferases CREB-binding protein (CBP) and E1A-associated protein p300 (p300).Finally, we discuss the potential of ameliorative strategies targeting CBP/p300 for the treatment of these disorders.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Neurociencias, Av. Santiago Ramon y Cajal s/n. Sant Joan d'Alacant 03550, Alicante, Spain.

ABSTRACT
Neuropsychiatric pathologies, including neurodegenerative diseases and neurodevelopmental syndromes, are frequently associated with dysregulation of various essential cellular mechanisms, such as transcription, mitochondrial respiration and protein degradation. In these complex scenarios, it is difficult to pinpoint the specific molecular dysfunction that initiated the pathology or that led to the fatal cascade of events that ends with the death of the neuron. Among the possible original factors, epigenetic dysregulation has attracted special attention. This review focuses on two highly related epigenetic factors that are directly involved in a number of neurological disorders, the lysine acetyltransferases CREB-binding protein (CBP) and E1A-associated protein p300 (p300). We first comment on the role of chromatin acetylation and the enzymes that control it, particularly CBP and p300, in neuronal plasticity and cognition. Next, we describe the involvement of these proteins in intellectual disability and in different neurodegenerative diseases. Finally, we discuss the potential of ameliorative strategies targeting CBP/p300 for the treatment of these disorders.

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Structure of KAT3 proteins. CBP and p300 share a number of structural domains including three cysteine/histidine rich regions (CH1-CH3) forprotein-protein interaction, the KIX domain that mediates the interaction with CREB and other transcription factors, and the KAT domain. The domains ofhighest homology and the percentage of amino acid identity between the two proteins are indicated. Regions of high homology between the human CBP andp300 proteins expressed as % identity. NRID, nuclear hormone receptor interacting domain; CH1-3, cysteine/histidine-rich regions 1-3; TAZ1-2, transcriptionaladaptor Zn-finger domain 1-2; KIX, kinase inducible domain; Br, bromodomain; PHD, plant homeodomain; ZZ, ZZ-type Zn-finger domain; SID, SRC-1 interacting domain; MDM2, p53 E3-ubiquitin protein ligase homolog; ATF, activation transcription factors; TBP, TATA-binding protein. Figure modifiedfrom [52].
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Figure 2: Structure of KAT3 proteins. CBP and p300 share a number of structural domains including three cysteine/histidine rich regions (CH1-CH3) forprotein-protein interaction, the KIX domain that mediates the interaction with CREB and other transcription factors, and the KAT domain. The domains ofhighest homology and the percentage of amino acid identity between the two proteins are indicated. Regions of high homology between the human CBP andp300 proteins expressed as % identity. NRID, nuclear hormone receptor interacting domain; CH1-3, cysteine/histidine-rich regions 1-3; TAZ1-2, transcriptionaladaptor Zn-finger domain 1-2; KIX, kinase inducible domain; Br, bromodomain; PHD, plant homeodomain; ZZ, ZZ-type Zn-finger domain; SID, SRC-1 interacting domain; MDM2, p53 E3-ubiquitin protein ligase homolog; ATF, activation transcription factors; TBP, TATA-binding protein. Figure modifiedfrom [52].

Mentions: KAT3 proteins have diverse functions related to transcription activation and regulation. Thus, they are usually described as molecular scaffolds that bring different proteins together to the promoters. Their large size (over 2400 aas) and modular organization enable interaction with several proteins at the same time. For example, the interaction of CBP with MAPKs and the E-Cdk2 complex not only promotes the phosphorylation of CBP but also the phosphorylation of several CBP-interacting transcription factors [48, 49]. The following domains can be distinguished in both CBP and p300 (Fig. 2): (i) three cysteine/histidine-rich regions (CH1 to CH3) that bind zinc and are involved in protein-protein interactions; (ii) a lysine acetyltransferase (KAT) domain in the center of the protein; (iii) a bromodomain (BD) that binds acetylated lysines in histones and specific transcription factors [50]; (iv) two transactivation domains located at either end of the protein; and (v) multiple specific interaction domains for different transcription factors, such as the KIX domain that mediates the interaction between CBP/p300 and CREB phosphorylated at Ser133 [51]. An important consequence of this structure is that CBP/p300 can act as a molecular bridge between DNA-binding transcription factors and components of the basal transcription machinery, such as the TATA-box-binding protein (TBP) and the RNApol II complex. In addition, the KAT activity of CBP/p300 can relax the configuration of the chromatin around the bound DNA sequences by acetylation of histones. These are thought to be the molecular mechanisms responsible for the function of KAT3 proteins as transcriptional co-activators.


Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders.

Valor LM, Viosca J, Lopez-Atalaya JP, Barco A - Curr. Pharm. Des. (2013)

Structure of KAT3 proteins. CBP and p300 share a number of structural domains including three cysteine/histidine rich regions (CH1-CH3) forprotein-protein interaction, the KIX domain that mediates the interaction with CREB and other transcription factors, and the KAT domain. The domains ofhighest homology and the percentage of amino acid identity between the two proteins are indicated. Regions of high homology between the human CBP andp300 proteins expressed as % identity. NRID, nuclear hormone receptor interacting domain; CH1-3, cysteine/histidine-rich regions 1-3; TAZ1-2, transcriptionaladaptor Zn-finger domain 1-2; KIX, kinase inducible domain; Br, bromodomain; PHD, plant homeodomain; ZZ, ZZ-type Zn-finger domain; SID, SRC-1 interacting domain; MDM2, p53 E3-ubiquitin protein ligase homolog; ATF, activation transcription factors; TBP, TATA-binding protein. Figure modifiedfrom [52].
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3722569&req=5

Figure 2: Structure of KAT3 proteins. CBP and p300 share a number of structural domains including three cysteine/histidine rich regions (CH1-CH3) forprotein-protein interaction, the KIX domain that mediates the interaction with CREB and other transcription factors, and the KAT domain. The domains ofhighest homology and the percentage of amino acid identity between the two proteins are indicated. Regions of high homology between the human CBP andp300 proteins expressed as % identity. NRID, nuclear hormone receptor interacting domain; CH1-3, cysteine/histidine-rich regions 1-3; TAZ1-2, transcriptionaladaptor Zn-finger domain 1-2; KIX, kinase inducible domain; Br, bromodomain; PHD, plant homeodomain; ZZ, ZZ-type Zn-finger domain; SID, SRC-1 interacting domain; MDM2, p53 E3-ubiquitin protein ligase homolog; ATF, activation transcription factors; TBP, TATA-binding protein. Figure modifiedfrom [52].
Mentions: KAT3 proteins have diverse functions related to transcription activation and regulation. Thus, they are usually described as molecular scaffolds that bring different proteins together to the promoters. Their large size (over 2400 aas) and modular organization enable interaction with several proteins at the same time. For example, the interaction of CBP with MAPKs and the E-Cdk2 complex not only promotes the phosphorylation of CBP but also the phosphorylation of several CBP-interacting transcription factors [48, 49]. The following domains can be distinguished in both CBP and p300 (Fig. 2): (i) three cysteine/histidine-rich regions (CH1 to CH3) that bind zinc and are involved in protein-protein interactions; (ii) a lysine acetyltransferase (KAT) domain in the center of the protein; (iii) a bromodomain (BD) that binds acetylated lysines in histones and specific transcription factors [50]; (iv) two transactivation domains located at either end of the protein; and (v) multiple specific interaction domains for different transcription factors, such as the KIX domain that mediates the interaction between CBP/p300 and CREB phosphorylated at Ser133 [51]. An important consequence of this structure is that CBP/p300 can act as a molecular bridge between DNA-binding transcription factors and components of the basal transcription machinery, such as the TATA-box-binding protein (TBP) and the RNApol II complex. In addition, the KAT activity of CBP/p300 can relax the configuration of the chromatin around the bound DNA sequences by acetylation of histones. These are thought to be the molecular mechanisms responsible for the function of KAT3 proteins as transcriptional co-activators.

Bottom Line: Among the possible original factors, epigenetic dysregulation has attracted special attention.This review focuses on two highly related epigenetic factors that are directly involved in a number of neurological disorders, the lysine acetyltransferases CREB-binding protein (CBP) and E1A-associated protein p300 (p300).Finally, we discuss the potential of ameliorative strategies targeting CBP/p300 for the treatment of these disorders.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Neurociencias, Av. Santiago Ramon y Cajal s/n. Sant Joan d'Alacant 03550, Alicante, Spain.

ABSTRACT
Neuropsychiatric pathologies, including neurodegenerative diseases and neurodevelopmental syndromes, are frequently associated with dysregulation of various essential cellular mechanisms, such as transcription, mitochondrial respiration and protein degradation. In these complex scenarios, it is difficult to pinpoint the specific molecular dysfunction that initiated the pathology or that led to the fatal cascade of events that ends with the death of the neuron. Among the possible original factors, epigenetic dysregulation has attracted special attention. This review focuses on two highly related epigenetic factors that are directly involved in a number of neurological disorders, the lysine acetyltransferases CREB-binding protein (CBP) and E1A-associated protein p300 (p300). We first comment on the role of chromatin acetylation and the enzymes that control it, particularly CBP and p300, in neuronal plasticity and cognition. Next, we describe the involvement of these proteins in intellectual disability and in different neurodegenerative diseases. Finally, we discuss the potential of ameliorative strategies targeting CBP/p300 for the treatment of these disorders.

Show MeSH
Related in: MedlinePlus