inzicht - Molecular Biology - # Mechanism of mRNA Export Mediated by the CBC-ALYREF Complex

Structural Insights into the Interaction between the Nuclear Cap Binding Complex and the mRNA Export Factor ALYREF

Q: How might the dysregulation of the CBC-ALYREF interaction contribute to the development of certain cancers?

Dysregulation of the interaction between the Cap-Binding Complex (CBC) and Aly/REF (ALYREF) can have significant implications for cancer development. The CBC is known to play crucial roles in mRNA metabolism, including transcription, splicing, and export. ALYREF, on the other hand, is a key mRNA export factor that links the Transcription-Export (TREX) complex to the 5' end of mRNA. Mutations in the residues of the CBC that interface with ALYREF have been identified in various forms of cancer. For example, mutations in NCBP1 and NCBP2 have been associated with certain cancers. These mutations can potentially disrupt the interaction between ALYREF and the CBC, leading to dysregulation of mRNA export and other processes coordinated by these proteins. ALYREF itself has been found to be frequently upregulated in cancerous tissues. If the interaction between ALYREF and the CBC is compromised due to mutations or dysregulation, it can impact mRNA export efficiency, gene expression, and other cellular processes. This dysregulation can contribute to the development and progression of certain cancers by altering the expression of key genes involved in cell growth, proliferation, and survival.

Q: What are the potential implications of the mutually exclusive binding of ALYREF to the CBC and the EJC for the coordination of mRNA processing and export?

The mutually exclusive binding of ALYREF to the CBC and the Exon Junction Complex (EJC) has important implications for the coordination of mRNA processing and export. ALYREF plays a central role in recruiting the mRNA export machinery to the 5' end of mRNA through its interactions with both the CBC and the EJC. The structural insights into the CBC-ALYREF interaction reveal that the binding interfaces of ALYREF with the CBC and the EJC are not compatible, suggesting that ALYREF can only interact with one complex at a time. This exclusivity in binding implies a sequential recruitment model where ALYREF dissociates from the CBC before interacting with the EJC or vice versa. This sequential recruitment model ensures the proper coordination of mRNA processing and export. After ALYREF recruits the mRNA export machinery to the 5' end of mRNA through its interaction with the CBC, it can transfer to other sites enriched with export factors and participate in different complexes located along the mRNA. This sequential recruitment and dissociation process likely facilitates efficient mRNA export and ensures the proper functioning of the mRNA processing and export machinery.

Q: Could the structural insights into the CBC-ALYREF interaction be leveraged to develop novel antiviral therapies targeting the hijacking of host mRNA export pathways by viral proteins?

The structural insights into the interaction between the Cap-Binding Complex (CBC) and Aly/REF (ALYREF) could indeed be leveraged to develop novel antiviral therapies targeting the hijacking of host mRNA export pathways by viral proteins. Viruses such as Herpes simplex virus (HSV-1) and Herpesvirus saimiri (HVS) exploit the host mRNA export machinery by targeting ALYREF and disrupting its interactions with the CBC. By understanding the specific binding interfaces between ALYREF and the CBC, as well as how viral proteins like ICP27 and ORF57 interfere with this interaction, researchers can design targeted therapies to disrupt the viral hijacking of host mRNA export pathways. For example, small molecules or peptides that mimic the binding interfaces between ALYREF and the CBC could potentially block the interaction between ALYREF and viral proteins, preventing the viral proteins from hijacking the mRNA export machinery. Additionally, targeting the specific regions of ALYREF or the CBC that are critical for the interaction with viral proteins could provide a strategy to disrupt the viral hijacking mechanism. By developing compounds that interfere with these interactions, it may be possible to inhibit viral mRNA export and replication, offering a novel approach to antiviral therapy.

Belangrijkste concepten

The cryo-EM structure of the CBC-ALYREF complex reveals that the RRM domain of ALYREF binds to both the NCBP1 and NCBP2 subunits of the CBC, providing molecular insights into how ALYREF recruits the mRNA export machinery to the 5' end of transcripts.

Samenvatting

The nuclear cap binding complex (CBC) plays a crucial role in multiple steps of mRNA metabolism, including transcription, splicing, polyadenylation, and nuclear export. The CBC promotes mRNA export through its direct interaction with the key export factor ALYREF, which in turn links the TREX complex to the 5' end of mRNAs.

The authors present the first cryo-EM structure of the CBC in complex with ALYREF. The structure reveals that the RRM domain of ALYREF makes direct contacts with both the NCBP1 and NCBP2 subunits of the CBC. This interaction allows ALYREF to recruit the TREX complex and the export receptor NXF1-NXT1 to the 5' end of mRNAs, facilitating their nuclear export.

Structural comparisons show that the CBC-ALYREF interaction is incompatible with ALYREF's binding to the exon junction complex (EJC), suggesting that ALYREF's interactions with the CBC and EJC are mutually exclusive. This indicates a coordinated handoff of mRNPs from the CBC to the EJC during mRNA maturation and export.

The authors also discuss how viral proteins, such as HSV-1 ICP27 and HVS ORF57, can hijack the CBC-ALYREF interaction to promote the export of viral mRNAs. Overall, the structural insights provided in this study advance the understanding of the molecular mechanisms underlying mRNA export and its regulation by cellular and viral factors.

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Statistieken

"The CBC-mALYREF2 structure reveals that the RRM domain of mALYREF2 makes direct contact with both the NCBP1 and NCBP2 subunits of the CBC."
"Structural overlay of CBC-ALYREF and EJC-ALYREF reveals that both the CBC and the EJC bind to the RRM domain of ALYREF in a mutually exclusive manner."

Citaten

"The cryo-EM structure of CBC-ALYREF reveals that the RRM domain of ALYREF makes direct contact with both the NCBP1 and NCBP2 subunits of the CBC."
"Structural comparison between CBC-ALYREF, ALYREF-ICP27, and ALYREF-ORF57 reveals that the interface between ALYREF's RRM domain with the CBC is not compatible with the ICP27/ORF57-ALYREF interactions."

Belangrijkste Inzichten Gedestilleerd Uit

Cryo-EM structure of the CBC-ALYREF complex

by Clarke,B. P.... om www.biorxiv.org 10-02-2023

https://www.biorxiv.org/content/10.1101/2023.10.01.559959v2

Diepere vragen

How might the dysregulation of the CBC-ALYREF interaction contribute to the development of certain cancers?

Dysregulation of the interaction between the Cap-Binding Complex (CBC) and Aly/REF (ALYREF) can have significant implications for cancer development. The CBC is known to play crucial roles in mRNA metabolism, including transcription, splicing, and export. ALYREF, on the other hand, is a key mRNA export factor that links the Transcription-Export (TREX) complex to the 5' end of mRNA.
Mutations in the residues of the CBC that interface with ALYREF have been identified in various forms of cancer. For example, mutations in NCBP1 and NCBP2 have been associated with certain cancers. These mutations can potentially disrupt the interaction between ALYREF and the CBC, leading to dysregulation of mRNA export and other processes coordinated by these proteins.
ALYREF itself has been found to be frequently upregulated in cancerous tissues. If the interaction between ALYREF and the CBC is compromised due to mutations or dysregulation, it can impact mRNA export efficiency, gene expression, and other cellular processes. This dysregulation can contribute to the development and progression of certain cancers by altering the expression of key genes involved in cell growth, proliferation, and survival.

What are the potential implications of the mutually exclusive binding of ALYREF to the CBC and the EJC for the coordination of mRNA processing and export?

The mutually exclusive binding of ALYREF to the CBC and the Exon Junction Complex (EJC) has important implications for the coordination of mRNA processing and export. ALYREF plays a central role in recruiting the mRNA export machinery to the 5' end of mRNA through its interactions with both the CBC and the EJC.
The structural insights into the CBC-ALYREF interaction reveal that the binding interfaces of ALYREF with the CBC and the EJC are not compatible, suggesting that ALYREF can only interact with one complex at a time. This exclusivity in binding implies a sequential recruitment model where ALYREF dissociates from the CBC before interacting with the EJC or vice versa.
This sequential recruitment model ensures the proper coordination of mRNA processing and export. After ALYREF recruits the mRNA export machinery to the 5' end of mRNA through its interaction with the CBC, it can transfer to other sites enriched with export factors and participate in different complexes located along the mRNA. This sequential recruitment and dissociation process likely facilitates efficient mRNA export and ensures the proper functioning of the mRNA processing and export machinery.

Could the structural insights into the CBC-ALYREF interaction be leveraged to develop novel antiviral therapies targeting the hijacking of host mRNA export pathways by viral proteins?

The structural insights into the interaction between the Cap-Binding Complex (CBC) and Aly/REF (ALYREF) could indeed be leveraged to develop novel antiviral therapies targeting the hijacking of host mRNA export pathways by viral proteins. Viruses such as Herpes simplex virus (HSV-1) and Herpesvirus saimiri (HVS) exploit the host mRNA export machinery by targeting ALYREF and disrupting its interactions with the CBC.
By understanding the specific binding interfaces between ALYREF and the CBC, as well as how viral proteins like ICP27 and ORF57 interfere with this interaction, researchers can design targeted therapies to disrupt the viral hijacking of host mRNA export pathways. For example, small molecules or peptides that mimic the binding interfaces between ALYREF and the CBC could potentially block the interaction between ALYREF and viral proteins, preventing the viral proteins from hijacking the mRNA export machinery.
Additionally, targeting the specific regions of ALYREF or the CBC that are critical for the interaction with viral proteins could provide a strategy to disrupt the viral hijacking mechanism. By developing compounds that interfere with these interactions, it may be possible to inhibit viral mRNA export and replication, offering a novel approach to antiviral therapy.