Limits...
A U1 snRNP-specific assembly pathway reveals the SMN complex as a versatile hub for RNP exchange.

So BR, Wan L, Zhang Z, Li P, Babiash E, Duan J, Younis I, Dreyfuss G - Nat. Struct. Mol. Biol. (2016)

Bottom Line: In Sm-core assembly, a key snRNP-biogenesis step mediated by the SMN complex, the snRNA-specific RNA-binding protein (RBP) Gemin5 delivers pre-snRNAs, which join SMN-Gemin2-recruited Sm proteins.U1-70K hijacks SMN-Gemin2-Sm, enhancing Sm-core assembly on U1s and inhibiting that on other snRNAs, thereby promoting U1 overabundance and regulating snRNP repertoire.We propose that SMN-Gemin2 is a versatile hub for RNP exchange that functions broadly in RNA metabolism.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

ABSTRACT
Despite equal snRNP stoichiometry in spliceosomes, U1 snRNP (U1) is typically the most abundant vertebrate snRNP. Mechanisms regulating U1 overabundance and snRNP repertoire are unknown. In Sm-core assembly, a key snRNP-biogenesis step mediated by the SMN complex, the snRNA-specific RNA-binding protein (RBP) Gemin5 delivers pre-snRNAs, which join SMN-Gemin2-recruited Sm proteins. We show that the human U1-specific RBP U1-70K can bridge pre-U1 to SMN-Gemin2-Sm, in a Gemin5-independent manner, thus establishing an additional and U1-exclusive Sm core-assembly pathway. U1-70K hijacks SMN-Gemin2-Sm, enhancing Sm-core assembly on U1s and inhibiting that on other snRNAs, thereby promoting U1 overabundance and regulating snRNP repertoire. SMN-Gemin2's ability to facilitate transactions between different RBPs and RNAs explains its multi-RBP valency and the myriad transcriptome perturbations associated with SMN deficiency in neurodegenerative spinal muscular atrophy. We propose that SMN-Gemin2 is a versatile hub for RNP exchange that functions broadly in RNA metabolism.

Show MeSH

Related in: MedlinePlus

Schematic representation of SMN-Gemin2’s function as a versatile hub for RNP exchangeThe different colored spheres represent the diverse RBPs that bind multivalent SMN-Gemin2. For simplicity, only the pre-snRNAs’ key features relevant to this pathway are shown. (a) Gemin5, which recognizes the snRNP code common to all pre-snRNAs, is a drop-and-go donor that does not remain with the fully assembled Sm core. (b) U1-70K, a pre-U1’s stem-loop 1 (SL1) binding protein associates with the SMN-Gemin2 and remains part of the completed Sm core. (c) A representative and hypothetical RNP, exemplified by FUS/TLS, associates with the SMN-Gemin2 as described in the text.
© Copyright Policy - permissions-link
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4834709&req=5

Figure 5: Schematic representation of SMN-Gemin2’s function as a versatile hub for RNP exchangeThe different colored spheres represent the diverse RBPs that bind multivalent SMN-Gemin2. For simplicity, only the pre-snRNAs’ key features relevant to this pathway are shown. (a) Gemin5, which recognizes the snRNP code common to all pre-snRNAs, is a drop-and-go donor that does not remain with the fully assembled Sm core. (b) U1-70K, a pre-U1’s stem-loop 1 (SL1) binding protein associates with the SMN-Gemin2 and remains part of the completed Sm core. (c) A representative and hypothetical RNP, exemplified by FUS/TLS, associates with the SMN-Gemin2 as described in the text.

Mentions: Previous studies had suggested that the SMN complex is a dedicated Sm core assembly device that operates with a single RBP, Gemin5, which binds a single RNA structure, the snRNP code, and joins the SMN-Gemin2 subunit20,25. However, our studies demonstrate that SMN-Gemin2 can receive RNAs from at least one additional and structurally unrelated RBP (U1-70K) that has a different RNA-binding specificity (SL1). In Gemin5’s case there is a complete exchange between the RBP donor and the acceptor RBPs, Sm5. In contrast, U1-70K remains part of the mature RNP. Yet both paths use SMN-Gemin2, revealing SMN-Gemin2 as a versatile platform for RBP-RNA transactions. SMN-Gemin2 RNP exchange function leverages the donor’s RNA specificity to produce a specific RNP, in this case Sm core that the Sm proteins on their own could not44. We refer to this function as RNP exchange and propose that SMN-Gemin2’s RNP exchange function provides a unifying theme that extends beyond Sm core assembly to play a central role in RNA metabolism. Our concept of SMN-Gemin2 as a general RNP exchange, represented in Fig. 5, rests on its ability to bind many RBPs and RNAs, which increases the opportunity for creating a greater RNP diversity, and explains many previous observations.


A U1 snRNP-specific assembly pathway reveals the SMN complex as a versatile hub for RNP exchange.

So BR, Wan L, Zhang Z, Li P, Babiash E, Duan J, Younis I, Dreyfuss G - Nat. Struct. Mol. Biol. (2016)

Schematic representation of SMN-Gemin2’s function as a versatile hub for RNP exchangeThe different colored spheres represent the diverse RBPs that bind multivalent SMN-Gemin2. For simplicity, only the pre-snRNAs’ key features relevant to this pathway are shown. (a) Gemin5, which recognizes the snRNP code common to all pre-snRNAs, is a drop-and-go donor that does not remain with the fully assembled Sm core. (b) U1-70K, a pre-U1’s stem-loop 1 (SL1) binding protein associates with the SMN-Gemin2 and remains part of the completed Sm core. (c) A representative and hypothetical RNP, exemplified by FUS/TLS, associates with the SMN-Gemin2 as described in the text.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4834709&req=5

Figure 5: Schematic representation of SMN-Gemin2’s function as a versatile hub for RNP exchangeThe different colored spheres represent the diverse RBPs that bind multivalent SMN-Gemin2. For simplicity, only the pre-snRNAs’ key features relevant to this pathway are shown. (a) Gemin5, which recognizes the snRNP code common to all pre-snRNAs, is a drop-and-go donor that does not remain with the fully assembled Sm core. (b) U1-70K, a pre-U1’s stem-loop 1 (SL1) binding protein associates with the SMN-Gemin2 and remains part of the completed Sm core. (c) A representative and hypothetical RNP, exemplified by FUS/TLS, associates with the SMN-Gemin2 as described in the text.
Mentions: Previous studies had suggested that the SMN complex is a dedicated Sm core assembly device that operates with a single RBP, Gemin5, which binds a single RNA structure, the snRNP code, and joins the SMN-Gemin2 subunit20,25. However, our studies demonstrate that SMN-Gemin2 can receive RNAs from at least one additional and structurally unrelated RBP (U1-70K) that has a different RNA-binding specificity (SL1). In Gemin5’s case there is a complete exchange between the RBP donor and the acceptor RBPs, Sm5. In contrast, U1-70K remains part of the mature RNP. Yet both paths use SMN-Gemin2, revealing SMN-Gemin2 as a versatile platform for RBP-RNA transactions. SMN-Gemin2 RNP exchange function leverages the donor’s RNA specificity to produce a specific RNP, in this case Sm core that the Sm proteins on their own could not44. We refer to this function as RNP exchange and propose that SMN-Gemin2’s RNP exchange function provides a unifying theme that extends beyond Sm core assembly to play a central role in RNA metabolism. Our concept of SMN-Gemin2 as a general RNP exchange, represented in Fig. 5, rests on its ability to bind many RBPs and RNAs, which increases the opportunity for creating a greater RNP diversity, and explains many previous observations.

Bottom Line: In Sm-core assembly, a key snRNP-biogenesis step mediated by the SMN complex, the snRNA-specific RNA-binding protein (RBP) Gemin5 delivers pre-snRNAs, which join SMN-Gemin2-recruited Sm proteins.U1-70K hijacks SMN-Gemin2-Sm, enhancing Sm-core assembly on U1s and inhibiting that on other snRNAs, thereby promoting U1 overabundance and regulating snRNP repertoire.We propose that SMN-Gemin2 is a versatile hub for RNP exchange that functions broadly in RNA metabolism.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

ABSTRACT
Despite equal snRNP stoichiometry in spliceosomes, U1 snRNP (U1) is typically the most abundant vertebrate snRNP. Mechanisms regulating U1 overabundance and snRNP repertoire are unknown. In Sm-core assembly, a key snRNP-biogenesis step mediated by the SMN complex, the snRNA-specific RNA-binding protein (RBP) Gemin5 delivers pre-snRNAs, which join SMN-Gemin2-recruited Sm proteins. We show that the human U1-specific RBP U1-70K can bridge pre-U1 to SMN-Gemin2-Sm, in a Gemin5-independent manner, thus establishing an additional and U1-exclusive Sm core-assembly pathway. U1-70K hijacks SMN-Gemin2-Sm, enhancing Sm-core assembly on U1s and inhibiting that on other snRNAs, thereby promoting U1 overabundance and regulating snRNP repertoire. SMN-Gemin2's ability to facilitate transactions between different RBPs and RNAs explains its multi-RBP valency and the myriad transcriptome perturbations associated with SMN deficiency in neurodegenerative spinal muscular atrophy. We propose that SMN-Gemin2 is a versatile hub for RNP exchange that functions broadly in RNA metabolism.

Show MeSH
Related in: MedlinePlus