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== Structure == | == Structure == | ||
As all the TIF1 proteins, KAP-1 owns a N-terminal tripartite motif (TRIM). This motif is a protein-protein interface which contains an RBCC domain (itself composed of a Ring finger, two B-box zinc fingers, and a coiled-coil domain) and a central TIF1 signature sequence (TSS). [3]KAP-1 has a C-terminal motif composed of one homeodomain (PHD) and one bromodomain. Moreover, KAP-1 possesses a central binding domain called HP1 (for heterochromatin protein 1). | As all the TIF1 proteins, KAP-1 owns a N-terminal tripartite motif (TRIM). This motif is a protein-protein interface which contains an RBCC domain (itself composed of a Ring finger, two B-box zinc fingers, and a coiled-coil domain) and a central TIF1 signature sequence (TSS).[3] KAP-1 has a C-terminal motif composed of one homeodomain (PHD) and one bromodomain. Moreover, KAP-1 possesses a central binding domain called HP1 (for heterochromatin protein 1). | ||
As said before, the fisrt part of KAP-1 is the N-Terminal motif, within we can find the RBCC sequence. The RBCC domain has a high affinity for protein interactions. Thus, this is the RBCC domain which alllows the interaction between KAP-1 and the 3 -ends of ZNF genes of KRAB-ZNFs domains. In this way, KAP-1 binds as a homotrimer to a single KRAB domain. There is then an oligomerization which provides folding of the KRAB domain to encapsulates it in a protease-resistant core. RBCC is composed of three subdomains. One of these is the ring subdomain. This is a double zinc-binding C<sub>3</sub>HC<sub>4</sub> motif. The second subdomain is composed of the two B-box which are cysteine-rich zinc-binding motif of the form CHC<sub>3</sub>H<sub>2</sub>. These latter interacts with the last subdomain : the coiled-coil domain. These two subdomains form an extended hydrophobic helical region. It’s here that protein-protein interactions take place. Next to the RBCC motif, there is the TSS sequence which is tryptophan and phenylalanine rich. We know that the deletion of this sequence cancel the transcriptional repression mediated by TIF1γ. [4] | As said before, the fisrt part of KAP-1 is the N-Terminal motif, within we can find the RBCC sequence. The RBCC domain has a high affinity for protein interactions. Thus, this is the RBCC domain which alllows the interaction between KAP-1 and the 3 -ends of ZNF genes of KRAB-ZNFs domains. In this way, KAP-1 binds as a homotrimer to a single KRAB domain. There is then an oligomerization which provides folding of the KRAB domain to encapsulates it in a protease-resistant core. RBCC is composed of three subdomains. One of these is the ring subdomain. This is a double zinc-binding C<sub>3</sub>HC<sub>4</sub> motif. The second subdomain is composed of the two B-box which are cysteine-rich zinc-binding motif of the form CHC<sub>3</sub>H<sub>2</sub>. These latter interacts with the last subdomain : the coiled-coil domain. These two subdomains form an extended hydrophobic helical region. It’s here that protein-protein interactions take place. Next to the RBCC motif, there is the TSS sequence which is tryptophan and phenylalanine rich. We know that the deletion of this sequence cancel the transcriptional repression mediated by TIF1γ. [4] | ||
Between the N-Terminal and the C-Terminal motif, KAP-1 owns a HP1 binding domain which is a hydrophobic PxVxL pentapeptide. This pentapeptide allows the interaction of KAP-1 with the chromoshadow domain of all the proteins of the HP1 family. This is necessary for the repression of reporter genes. This domain is proline, glycine and serine rich. [4] | Between the N-Terminal and the C-Terminal motif, KAP-1 owns a HP1 binding domain which is a hydrophobic PxVxL pentapeptide. This pentapeptide allows the interaction of KAP-1 with the chromoshadow domain of all the proteins of the HP1 family. This is necessary for the repression of reporter genes. This domain is proline, glycine and serine rich. [4] | ||
Finally, the last part of KAP-1, which is the C-terminal motif, is the tandem formed by the PHD and the bromodomain (or PB domain). These two motifs are both very important and are closely associated to play a role in the transcriptional repression. [4] | Finally, the last part of KAP-1, which is the C-terminal motif, is the tandem formed by the PHD and the bromodomain (or PB domain). These two motifs are both very important and are closely associated to play a role in the transcriptional repression.[4] | ||
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== Importance of the tandem PHD-Bromodomain == | == Importance of the tandem PHD-Bromodomain == | ||
Kap-1 structure have a tandem PHD finger- bromodomain. This tandem is implicate in the repression of specific gene. The tandem is formed with the first helix, of an atypical bromodomain which forms a central hydrophobic core. Hence, three helix of the bromodomain and the zinc binding PHD finger are anchored in the central core. The bromodomain adopt four helix bundle (100 amino-acid) and the PHD finger contain an antiparallel sheet Béta (60 amino-acid). [2] Sumoylated Kap-1 is the highly repressive form. That’s why the adjacent KAP-1 bromodomain is sumoylated by the PHD which functioning as an intramolecular E3 ligase. The bromodomain need to be sumoylate because it allows interaction with SETDB1 (SET domain, bifurcated 1) in order to stimule it H3K9me3 specific histone methyltransferase activity. The bromodomain can also interact with Mi2 which is an isoform of the Mi2 protein found in NuRD complex. [4] | Kap-1 structure have a tandem PHD finger- bromodomain. This tandem is implicate in the repression of specific gene. The tandem is formed with the first helix, of an atypical bromodomain which forms a central hydrophobic core. Hence, three helix of the bromodomain and the zinc binding PHD finger are anchored in the central core. The bromodomain adopt four helix bundle (100 amino-acid) and the PHD finger contain an antiparallel sheet Béta (60 amino-acid).[2] Sumoylated Kap-1 is the highly repressive form. That’s why the adjacent KAP-1 bromodomain is sumoylated by the PHD which functioning as an intramolecular E3 ligase. The bromodomain need to be sumoylate because it allows interaction with SETDB1 (SET domain, bifurcated 1) in order to stimule it H3K9me3 specific histone methyltransferase activity. The bromodomain can also interact with Mi2 which is an isoform of the Mi2 protein found in NuRD complex.[4] | ||
== Therapeutical perspective == | == Therapeutical perspective == | ||
KAP-1 can represent a good perspective for some therapies because it is implicate in the etablishment of viral latency, for example in the replication of Epstein-Barr Virus (EBV), Kaposi's sarcoma-associated herpes virus (KSHV), Human cytomegalovirus (HCMV) and for endogenous retroviruses. [7][8] Indeed, during the lytic infection, KAP-1 binds the viral genome and plays his role of repressor for the transcription of this genome (KAP-1 is activated when it is sumoylated and inactivate when it is phosphorylated). In this way, when KAP-1 is phosphorylated on serine 824 (by mTOR or ATM for example), it is not anymore able to recruit SETDB1 which is necessary to regulate the transcription. KAP-1 become thus inactive and the latency exits, and the viral genome will be transcribed and replicate. The result is so the switch from viral latency to the lytic cycle. The idea is then to use this characteristic of KAP-1 to develop a potential therapy able to purge the virus from infected individuals.[7][8][9] | KAP-1 can represent a good perspective for some therapies because it is implicate in the etablishment of viral latency, for example in the replication of Epstein-Barr Virus (EBV), Kaposi's sarcoma-associated herpes virus (KSHV), Human cytomegalovirus (HCMV) and for endogenous retroviruses. [7][8]Indeed, during the lytic infection, KAP-1 binds the viral genome and plays his role of repressor for the transcription of this genome (KAP-1 is activated when it is sumoylated and inactivate when it is phosphorylated). In this way, when KAP-1 is phosphorylated on serine 824 (by mTOR or ATM for example), it is not anymore able to recruit SETDB1 which is necessary to regulate the transcription. KAP-1 become thus inactive and the latency exits, and the viral genome will be transcribed and replicate. The result is so the switch from viral latency to the lytic cycle. The idea is then to use this characteristic of KAP-1 to develop a potential therapy able to purge the virus from infected individuals.[7][8][9] | ||
</StructureSection> | </StructureSection> | ||
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[8] Helen M. Rowe, Johan Jakobsson, Daniel Mesnard, Jacques Rougemont, Séverine Reynard, Tugce Aktas, Pierre V. Maillard, Hillary Layard-Liesching, Sonia Verp, Julien Marquis, François Spitz, Daniel B. Constam & Didier Trono, KAP1 controls endogenous retroviruses in embryonic stem cells, Nature, January 14, 2010. | [8] Helen M. Rowe, Johan Jakobsson, Daniel Mesnard, Jacques Rougemont, Séverine Reynard, Tugce Aktas, Pierre V. Maillard, Hillary Layard-Liesching, Sonia Verp, Julien Marquis, François Spitz, Daniel B. Constam & Didier Trono, KAP1 controls endogenous retroviruses in embryonic stem cells, Nature, January 14, 2010. | ||
[9]Andreia Lee, Oya Cingöz, Yosef Sabo, Stephen P. Goff, Characterization of interaction between Trim28 and YY1 in silencing proviral DNA of Moloney murine leukemia virus, Received for publication, August 20, 2017, Revised 10 January 2018, Accepted 12 January 2018, Published, Virology , February 23, 2018. | [9] Andreia Lee, Oya Cingöz, Yosef Sabo, Stephen P. Goff, Characterization of interaction between Trim28 and YY1 in silencing proviral DNA of Moloney murine leukemia virus, Received for publication, August 20, 2017, Revised 10 January 2018, Accepted 12 January 2018, Published, Virology , February 23, 2018. | ||