ข้อมูลเชิงลึก - Computational Biology - # Structure and Dynamics of the Human Systemic RNAi Defective Transmembrane Protein 1 (hSIDT1)

Structure of the Human Systemic RNAi Defective Transmembrane Protein 1 (hSIDT1) Reveals the Conformational Flexibility of its Lipid Binding Domain

Q: How do the conformational dynamics of the lipid binding domain (LBD) in hSIDT1 regulate its lipase activity and facilitate the transport of small non-coding RNAs?

The conformational dynamics of the lipid binding domain (LBD) in hSIDT1 play a crucial role in regulating its lipase activity and facilitating the transport of small non-coding RNAs. The LBD in hSIDT1 is a conformationally flexible domain that interacts with lipids, cholesterol, and potentially other molecules. This flexibility allows the LBD to adapt to different ligands and environments, influencing the protein's overall function. The LBD in hSIDT1 is believed to possess lipase activity, which is essential for lipid hydrolysis and potentially for the transport of small non-coding RNAs. The presence of a phenylalanine highway within the LBD suggests a role in lipid binding and transport. The LBD interacts with the transmembrane domain (TMD) core, forming a dynamic interface that may regulate the protein's overall activity. The binding of lipids, such as cholesterol or phospholipids, to the LBD can modulate its structure and function. These lipids may act as allosteric regulators, influencing the conformational dynamics of the LBD and potentially affecting its interaction with small non-coding RNAs. Changes in lipid binding can alter the accessibility of the RNA binding sites within the protein, impacting its ability to transport small RNAs across membranes. Overall, the conformational dynamics of the LBD in hSIDT1 are essential for regulating its lipase activity, lipid binding properties, and the transport of small non-coding RNAs. Understanding these dynamics is crucial for unraveling the molecular mechanisms underlying the protein's diverse functions.

Q: How do the potential allosteric mechanisms by which the binding of cholesterol or other lipids modulate the structure and function of hSIDT1?

The binding of cholesterol or other lipids to hSIDT1 can act as allosteric regulators, influencing the protein's structure and function through conformational changes and dynamic interactions. These potential allosteric mechanisms play a significant role in modulating the activity of hSIDT1 and its diverse biological functions. Structural Changes: The binding of cholesterol or lipids to hSIDT1 can induce structural changes in the protein, altering its conformation and affecting the arrangement of functional domains such as the lipid binding domain (LBD) and the transmembrane domain (TMD). These structural changes can impact the protein's ability to interact with other molecules, including small non-coding RNAs. Functional Regulation: Allosteric binding of cholesterol or lipids can regulate the enzymatic activity of hSIDT1, such as its lipase activity. By binding to specific sites within the protein, cholesterol or lipids can modulate the catalytic function of hSIDT1, influencing processes like lipid hydrolysis and potentially RNA transport. Dynamic Interactions: The allosteric binding of cholesterol or lipids can alter the dynamic interactions within hSIDT1, affecting its stability, oligomerization, and membrane interactions. These changes in protein dynamics can impact the protein's overall function and its role in cellular processes. Signal Transduction: Allosteric mechanisms triggered by lipid binding to hSIDT1 can also lead to signal transduction pathways, influencing gene expression, cellular responses, and metabolic activities. These signaling cascades can further regulate the protein's function in various biological contexts. By understanding the potential allosteric mechanisms involved in lipid binding to hSIDT1, researchers can uncover novel insights into the regulation of the protein's structure and function, paving the way for targeted therapeutic interventions in diseases associated with hSIDT1 dysregulation.

แนวคิดหลัก

The cryo-EM structure of the human systemic RNAi defective transmembrane protein 1 (hSIDT1) reveals a dimeric architecture with a flexible lipid binding domain (LBD) and a stable transmembrane domain (TMD) core, providing insights into the inherent conformational dynamics within the cholesterol uptake (ChUP) family of membrane proteins.

บทคัดย่อ

The content describes the cryo-EM structure determination and analysis of the human systemic RNAi defective transmembrane protein 1 (hSIDT1). Key highlights:

hSIDT1 exists as a dimer in vitro, with the dimer interface formed by interactions between the extra-cytosolic domain (ECD), transmembrane domain (TMD) core, and the lipid binding domain (LBD).
The ECD adopts a double jelly roll fold, while the TMD can be divided into a dynamic LBD and a more stable TMD core. The TMD core is stabilized by four tiers of interactions, including a conserved metal ion binding site and a phenylalanine highway.
Structural comparisons with other ChUP family members reveal that the LBD is the most flexible region, with significant conformational changes observed upon binding of different lipids. This flexibility in the LBD is believed to be crucial for the lipase activity and RNA transport functions of hSIDT1.
The ECD, particularly the interface between the two jelly roll domains, is proposed to be the primary site of RNA binding, while the LBD dynamics may facilitate the translocation of the bound RNA through the TMD.
The structural insights provide a framework for understanding the molecular mechanisms underlying the diverse biological functions of hSIDT1, including its roles in hepatocellular lipid homeostasis, glucose tolerance, tumor development, and innate immunity.

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biorxiv.org

สถิติ

hSIDT1 exists as a dimer in vitro, with the dimer interface spanning approximately 2800 Å2.
The extra-cytosolic domain (ECD) of hSIDT1 adopts a double jelly roll fold, with two tandem β-sandwich domains.
The transmembrane domain (TMD) of hSIDT1 can be divided into a dynamic lipid binding domain (LBD) and a more stable TMD core.
The TMD core is stabilized by four tiers of interactions, including a conserved metal ion binding site and a phenylalanine highway.

คำพูด

"The cryo-EM structure of hSIDT1 reveals a dimeric architecture with a flexible lipid binding domain (LBD) and a stable transmembrane domain (TMD) core."
"Structural comparisons with other ChUP family members suggest that the LBD is the most flexible region, with significant conformational changes observed upon binding of different lipids."
"The ECD, particularly the interface between the two jelly roll domains, is proposed to be the primary site of RNA binding, while the LBD dynamics may facilitate the translocation of the bound RNA through the TMD."

ข้อมูลเชิงลึกที่สำคัญจาก

Structure of the human systemic RNAi defective transmembrane protein 1 (hSIDT1) reveals the conformational flexibility of its lipid binding domain

by Navratna,V.,... ที่ www.biorxiv.org 12-23-2023

https://www.biorxiv.org/content/10.1101/2023.12.21.572875v2

สอบถามเพิ่มเติม

How do the conformational dynamics of the lipid binding domain (LBD) in hSIDT1 regulate its lipase activity and facilitate the transport of small non-coding RNAs?

The conformational dynamics of the lipid binding domain (LBD) in hSIDT1 play a crucial role in regulating its lipase activity and facilitating the transport of small non-coding RNAs. The LBD in hSIDT1 is a conformationally flexible domain that interacts with lipids, cholesterol, and potentially other molecules. This flexibility allows the LBD to adapt to different ligands and environments, influencing the protein's overall function.
The LBD in hSIDT1 is believed to possess lipase activity, which is essential for lipid hydrolysis and potentially for the transport of small non-coding RNAs. The presence of a phenylalanine highway within the LBD suggests a role in lipid binding and transport. The LBD interacts with the transmembrane domain (TMD) core, forming a dynamic interface that may regulate the protein's overall activity.
The binding of lipids, such as cholesterol or phospholipids, to the LBD can modulate its structure and function. These lipids may act as allosteric regulators, influencing the conformational dynamics of the LBD and potentially affecting its interaction with small non-coding RNAs. Changes in lipid binding can alter the accessibility of the RNA binding sites within the protein, impacting its ability to transport small RNAs across membranes.
Overall, the conformational dynamics of the LBD in hSIDT1 are essential for regulating its lipase activity, lipid binding properties, and the transport of small non-coding RNAs. Understanding these dynamics is crucial for unraveling the molecular mechanisms underlying the protein's diverse functions.

How do the potential allosteric mechanisms by which the binding of cholesterol or other lipids modulate the structure and function of hSIDT1?

The binding of cholesterol or other lipids to hSIDT1 can act as allosteric regulators, influencing the protein's structure and function through conformational changes and dynamic interactions. These potential allosteric mechanisms play a significant role in modulating the activity of hSIDT1 and its diverse biological functions.

Structural Changes: The binding of cholesterol or lipids to hSIDT1 can induce structural changes in the protein, altering its conformation and affecting the arrangement of functional domains such as the lipid binding domain (LBD) and the transmembrane domain (TMD). These structural changes can impact the protein's ability to interact with other molecules, including small non-coding RNAs.

Functional Regulation: Allosteric binding of cholesterol or lipids can regulate the enzymatic activity of hSIDT1, such as its lipase activity. By binding to specific sites within the protein, cholesterol or lipids can modulate the catalytic function of hSIDT1, influencing processes like lipid hydrolysis and potentially RNA transport.

Dynamic Interactions: The allosteric binding of cholesterol or lipids can alter the dynamic interactions within hSIDT1, affecting its stability, oligomerization, and membrane interactions. These changes in protein dynamics can impact the protein's overall function and its role in cellular processes.

Signal Transduction: Allosteric mechanisms triggered by lipid binding to hSIDT1 can also lead to signal transduction pathways, influencing gene expression, cellular responses, and metabolic activities. These signaling cascades can further regulate the protein's function in various biological contexts.

By understanding the potential allosteric mechanisms involved in lipid binding to hSIDT1, researchers can uncover novel insights into the regulation of the protein's structure and function, paving the way for targeted therapeutic interventions in diseases associated with hSIDT1 dysregulation.

Given the diverse biological roles of hSIDT1, how can the structural insights be leveraged to develop targeted therapies for diseases associated with dysregulation of hSIDT1, such as cancer, liver diseases, and metabolic disorders?

The structural insights into hSIDT1 provide valuable information that can be leveraged to develop targeted therapies for diseases associated with dysregulation of this protein, including cancer, liver diseases, and metabolic disorders. By understanding the molecular mechanisms underlying hSIDT1's diverse biological roles, researchers can identify potential therapeutic targets and design interventions to modulate the protein's function.

Drug Design: The structural details of hSIDT1 can guide the design of small molecule inhibitors or activators that target specific regions of the protein involved in its various functions. These compounds can modulate hSIDT1 activity, potentially offering new treatment options for diseases where hSIDT1 dysregulation plays a role.

Precision Medicine: Understanding the structural basis of hSIDT1's interactions with small non-coding RNAs, lipids, and other molecules can enable the development of personalized therapies that target specific pathways affected by hSIDT1 dysfunction. This approach can lead to more effective and tailored treatments for individual patients.

Therapeutic Targets: The identification of critical regions within hSIDT1 that are essential for its function in cancer, liver diseases, and metabolic disorders can highlight potential therapeutic targets. By focusing on these targets, researchers can develop novel therapies that specifically address the underlying mechanisms of disease.

Biologics Development: Structural insights into hSIDT1 can also inform the development of biologics, such as antibodies or RNA-based therapeutics, that target the protein or its interacting partners. These biologics can be designed to modulate hSIDT1 activity and function in a precise and targeted manner.

Overall, the structural insights into hSIDT1 offer a foundation for the development of innovative therapeutic strategies that aim to correct dysregulation of the protein in various disease contexts. By translating these insights into targeted therapies, researchers can potentially improve treatment outcomes for patients with conditions linked to hSIDT1 dysfunction.