Human 17S U2 small nuclear ribonucleoprotein
From Proteopedia
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PDB ID - 6Y5Q Course Code: BI3323-Aug2025
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The 17S U2 small nuclear ribonucleoprotein (snRNP) is a critical precursor complex in pre-mRNA splicing, primarily responsible for recognizing the intron branch-site adenosine (BS-A). Its structure is highly regulated, defining a pre-catalytic state that must undergo significant remodelling for splicing to occur.
Architectural Blueprint
The 17S U2 snRNP exhibits a bipartite structure linked by three molecular bridges, composed of a rigid core and flexible components:
- 5′ Domain (The Rigid Core) dominated by the SF3b complex (SF3B1, SF3B3, PHF5A, SF3B5). The overall SF3b core structure remains rigid and functional upon 17S U2 assembly. , a key protein, adopts an open conformation in this complex, making the binding site accessible to splicing modulators (e.g., pladienolide B).
- 3′ Domain (The Flexible Part) which contains the Sm core and stem–loops III–IV of the U2 snRNA, bound by the proteins U2-A′ and U2-B″ and is connected to the 5’ domain by three molecular bridges.
Sequestration of the Branch Site
A critical feature of the 17S U2 structure is the sequestration of the U2 snRNA region that interacts with the intron. This ensures recognition only occurs at the correct time. This is comprises of:
- Formation of the BSL: The U2 snRNA forms an 8 bp Branchpoint-interacting Stem-Loop (BSL) adjacent to the C-terminal HEAT repeats of SF3B1
- Inaccessible Loop: The BSL loop is tightly sandwiched between the C-terminal SF3B1 HEAT repeats, PRP5, and TAT-SF1, rendering it physically inaccessible and preventing premature pairing with the intron branch site
- Stabilizing Components: A short separator helix of SF3A3 enforces the BSL's 8 bp length, stabilizing its position with respect to SLIIa.
Role of Remodeling Factors (PRP5 and TAT-SF1)
The proteins PRP5 and TAT-SF1 are integral to the 17S U2 structure and are essential for controlling the conformational switch required for splicing.
- TAT-SF1's Inhibitory Role: TAT-SF1 is located directly at the BSL loop and interacts with the SF3B1 hinge region (HR15–HR16). It acts to stabilize the BSL's sequestered state and prevents the premature closure of the SF3B1 HEAT domain. Its removal is mandatory for stable U2-branch site helix formation.
- PRP5's RNP Remodeling Role: PRP5 engages SF3B1 and TAT-SF1, stabilizing the open SF3B1 conformation.
- PRP5's primary function is to drive RNP remodeling: its ATP hydrolysis is proposed to release the BSL-sequestering proteins, promoting TAT-SF1 displacement and enabling the initial formation of the U2–BS helix.
Spliceosome Activation and Disease Relevance
Productive splicing requires a major restructuring of the U2 snRNP driven by the displacement of BSL-associated proteins and a conformational change in SF3B1.
- Conformational Switch: Release of the BSL allows the U2 5′ region to rotate and form the extended U2–BS helix. This pairing and the subsequent docking of the BS-A trigger the SF3B1 HEAT domain to close around the U2–BS helix, forming a critical pocket that locks the complex into the active state.
- SF3B1 and Cancer: SF3B1 is a common mutational target in haematopoietic cancers. Many cancer-associated SF3B1 mutations cluster near HR6, adjacent to PRP5-interacting regions, suggesting these mutations may disrupt the crucial PRP5 binding and RNP remodeling steps, leading to splicing defects implicated in disease.
References
Zhang, Z., Will, C. L., Bertram, K., Dybkov, O., Hartmuth, K., Agafonov, D. E., Hofele, R., Urlaub, H., Kastner, B., Luhrmann, R., & Stark, H. (2020). Molecular architecture of the human 17S U2 snRNP. Nature, 583(7815), 310–313.
