Structure and Function of Drosha | Drosha-DGCR8 Protein Complex

In the intricate world of molecular machinery, the Drosha emerges as a key player, orchestrating the initial steps of microRNA (miRNA) biogenesis. The structure of this protein unveils a molecular architecture finely tuned for its essential function of recognizing and processing primary miRNA transcripts (pri-miRNAs).

Definition of Drosha:

Drosha, a key player in gene regulation, is an endoribonuclease enzyme responsible for initiating the processing of primary microRNA transcripts (pri-miRNAs) into precursor miRNAs (pre-miRNAs) in the nucleus.

This essential step marks the beginning of the intricate pathway leading to the generation of mature microRNAs, pivotal molecules in the post-transcriptional control of gene expression. Drosha’s precise cleavage activity exemplifies its significance in shaping the cellular symphony of gene regulation.

Structure:

The mechanism of pri-miRNA processing reveals a molecular ballet orchestrated by enzymatic players, with the Drosha-DGCR8 complex taking center stage.

**1. Drosha Protein:

• At the core of this protein complex is the Drosha protein, a multifaceted enzyme belonging to the RNase III family.
• It features two RNase III domains, which are essential for its endonuclease activity, facilitating the precise cleavage of pri-miRNAs.

**2. DGCR8 (DiGeorge Syndrome Critical Region 8) Protein:

• The collaboration between Drosha and the DGCR8 protein is pivotal in forming the functional Drosha complex.
• DGCR8 acts as a molecular partner, enhancing the specificity of the complex in recognizing pri-miRNAs.

**3. Double-Stranded RNA-Binding Domain (dsRBD):

• It is equipped with a double-stranded RNA-binding domain (dsRBD) that aids in the recognition of the double-stranded regions of pri-miRNAs.
• This domain plays a crucial role in the interaction with DGCR8 and ensures the accuracy of pri-miRNA binding.

**4. PAZ Domain:

• Another important component of the this protein is the PAZ domain.
• The PAZ domain contributes to the interaction between Drosha and DGCR8, influencing the precise positioning of the complex on pri-miRNA substrates.

**5. Conformational Dynamics:

• The structure of this protein complex is dynamic and undergoes conformational changes upon binding to pri-miRNAs.
• The interaction with DGCR8 induces a structural shift in Drosha, forming the active Microprocessor complex ready for cleavage.

**6. Subunit Interaction:

• The interaction between Drosha and DGCR8 is not just a physical association but involves a complex interplay of subunit interactions.
• These interactions are crucial for the stability and functionality of the Drosha complex during pri-miRNA recognition and cleavage.

**7. Nuclear Localization Signal (NLS):

• This protein contains a nuclear localization signal (NLS) that guides the complex to the nucleus where pri-miRNA processing occurs.
• The NLS ensures the precise subcellular localization of this protein complex, emphasizing its role in the nucleus.

Function:

The precision of the Drosha-DGCR8 complex ensures accurate cleavage, setting the stage for the subsequent steps in miRNA biogenesis.

1. Recognition of pri-miRNAs:
   • The primary function of it is to recognize and process pri-miRNAs, the initial transcripts of miRNA genes.
   • DGCR8, through its dsRBD domain, recognizes and binds to the single-stranded regions of pri-miRNAs.
2. Formation of the Microprocessor Complex:
   • DGCR8 binding induces a conformational change in it, leading to the formation of the active Microprocessor complex.
   • This complex is poised at the base of the pri-miRNA hairpin structure, ready for precise cleavage.
3. Cleavage at the Base of the Hairpin Structure:
   • The RNase III domains of this protein perform a precise cleavage at the base of the pri-miRNA hairpin.
   • This cleavage separates the pri-miRNA into two distinct fragments, yielding the precursor miRNA (pre-miRNA) with characteristic 2-nucleotide overhangs.
4. Quality Control and Strand Selection:
   • The cleavage products undergo a quality control check to ensure fidelity in processing.
   • One strand of the pre-miRNA is preferentially selected as the mature miRNA strand, while the other strand is often degraded.

In the processing of mi-RNA not only Drosha, Dicer also perform an important role. If you want to know about this then read the article: Structure and Function of Dicer Enzyme | Dicer MicroRNA.

Importance of Drosha:

While renowned for its role in the initiation of microRNA (miRNA) biogenesis and subsequent gene silencing, this protein complex unfolds into a multifaceted orchestrator influencing diverse cellular processes. This molecular machinery, comprising this protein and its partner DGCR8, extends its reach beyond mere gene silencing, engaging in an array of functions that contribute to the intricate symphony of cellular dynamics.

**1. Transposon and Genome Defense:

• This protein complex plays a pivotal role in defending the genome against invasive elements such as transposons.
• By contributing to the biogenesis of small interfering RNAs (siRNAs), Drosha aids in the surveillance and suppression of transposon activity, preserving genome integrity.

**2. Cellular Stress Response:

• In the face of cellular stressors, this protein complex steps into action, dynamically responding to environmental challenges.
• Its expression and activity can be modulated under conditions of stress, indicating a role in cellular adaptation and survival.

**3. Regulation of Developmental Processes:

• Beyond its involvement in miRNA biogenesis, this complex influences fundamental developmental processes.
• It participates in pathways that govern cell differentiation, tissue development, and embryonic morphogenesis, contributing to the intricacies of organismal development.

**4. Tissue Homeostasis and Repair:

• The Drosha complex is implicated in the maintenance of tissue homeostasis and repair mechanisms.
• Through its role in miRNA biogenesis, it contributes to the regulation of cellular processes crucial for tissue health and recovery from injuries.

**5. Neurological Functions:

• This protein complex has been found to play a vital role in the nervous system, influencing neurodevelopment and neuronal functions.
• Its involvement in processes like synaptogenesis underscores its significance in shaping the intricate wiring of the brain.

**6. Regulation of Cellular Proliferation and Differentiation:

• Drosha’s impact extends beyond gene silencing to the regulation of cellular proliferation and differentiation.
• By influencing the expression of genes involved in cell cycle progression and fate determination, this complex contributes to the finely tuned orchestration of cellular behavior.

**7. Implications in Aging:

• Emerging evidence suggests a connection between this protein complex and the aging process.
• It’s deficiency has been linked to premature aging in certain model organisms, pointing toward its potential role in modulating the rate of aging.

**8. Disease Associations:

• Dysregulation of this protein complex has been implicated in various diseases, including cancer and neurodevelopmental disorders.
• Its involvement in diverse cellular functions positions it as a potential player in the pathogenesis of conditions beyond those traditionally associated with gene silencing.

Another important point of mi-RNA pathway is RISC, if you want to know about it then read the article: RNA-Induced Silencing Complex (RISC) in siRNA and miRNA.

Diseases Associated With Drosha Complex

This protein complex, a pivotal player in microRNA (miRNA) biogenesis and gene regulation, plays a crucial role in maintaining cellular health. Dysregulation of this intricate molecular machinery has been linked to a spectrum of diseases, offering insights into the broader impact of this complex on human health.

**1. Cancer:

• One of the prominent areas where this complex dysregulation is observed is in cancer development.
• Altered expression levels of it and its cofactors have been documented in various cancer types. The dysregulation often leads to aberrant miRNA processing, impacting the delicate balance of gene expression that governs cellular proliferation, differentiation, and apoptosis.

**2. Neurodevelopmental Disorders:

• The intricate involvement of this complex in neurodevelopment extends its relevance to neurodevelopmental disorders.
• Mutations or dysregulation of this complex components have been associated with conditions such as autism spectrum disorders (ASD) and intellectual disabilities, underscoring its significance in shaping the developing nervous system.

**3. Cardiovascular Diseases:

• The role of this complex extends to cardiovascular health, with implications in heart-related conditions.
• Dysregulation of miRNAs processed by the Drosha complex has been linked to cardiovascular diseases, influencing processes such as angiogenesis, cardiac hypertrophy, and vascular function.

**4. Immune System Disorders:

• The intricate interplay between miRNAs and immune system regulation implicates the Drosha complex in immune-related disorders.
• Dysregulation of miRNAs processed by Drosha may contribute to autoimmune diseases, where the immune system mistakenly targets the body’s own tissues.
• Dysregulation of the Drosha complex has been implicated in autoimmune diseases.
• In conditions such as systemic lupus erythematosus (SLE), altered miRNA expression patterns associated with Drosha complex dysfunction may contribute to immune dysregulation and autoimmunity.

**5. Metabolic Disorders:

• Emerging research suggests a connection between the Drosha complex and metabolic disorders.
• Dysregulation of miRNAs involved in metabolic processes may contribute to conditions such as obesity and diabetes, highlighting the potential impact of Drosha complex dysfunction on systemic metabolism.
• In obesity and type 2 diabetes, dysregulation of miRNAs involved in metabolic processes processed by Drosha may contribute to systemic metabolic dysfunction.

**6. Hematological Disorders:

• Dysregulation of miRNAs processed by the Drosha complex has been implicated in hematological disorders.
• Conditions such as leukemia and lymphoma may exhibit aberrant miRNA expression patterns linked to Drosha complex dysfunction.

**7. Infectious Diseases:

• The Drosha complex, through its role in RNA processing, may influence host responses to viral infections.
• Altered Drosha complex activity has been observed in the context of viral infections, suggesting a potential link to the host’s ability to mount an effective antiviral response.
• The Drosha complex may influence host responses to viral infections.
• Altered Drosha complex activity has been observed in the context of viral infections such as hepatitis B and C, suggesting a potential role in the host’s antiviral defense mechanisms.

The Drosha emerges as a molecular linchpin with far-reaching implications for health and disease. Its intricate involvement in microRNA biogenesis extends beyond gene silencing, influencing diverse cellular processes. Dysregulation of the Drosha complex is implicated in conditions ranging from cancer and neurodevelopmental disorders to cardiovascular diseases and immune-related disorders.

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