SMN-mediated assembly of RNPs: a complex story

Meister, Gunter; Eggert, Christian; Fischer, Utz

doi:10.1016/s0962-8924(02)02371-1

Cited by 211 publications

(199 citation statements)

References 63 publications

Supporting

Mentioning

195

Contrasting

Unclassified

Order By: Relevance

“…Together with a small number of other proteins, called Gemins 2-8, it forms the SMN complex which mediates the cytoplasmic assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs) U1, U2, U4 and U5, their counterparts from the minor spliceosome (U11, U12, U4atac) and the U7 snRNP involved in histone RNA 3' end processing. [47][48][49][50][51][52] Besides this cytoplasmic function, the SMN complex is also found in nuclear foci, called gems (for gemini of Cajal bodies), which often colocalize with Cajal bodies. In these locations, the SMN complex is proposed to play a role in snRNP differentiation.…”

Section: The Importance Of Exon Definitionmentioning

confidence: 99%

Repair of pre-mRNA splicing

2010

View full text Add to dashboard Cite

Section: The Importance Of Exon Definitionmentioning

confidence: 99%

Repair of pre-mRNA splicing

2010

View full text Add to dashboard Cite

“…As well as Gemin2, the roles and the mechanisms of the other Gemin proteins in the SMN complex are not yet fully characterized, although recent analysis reveals that, in addition to the SMN protein, Gemin3, -5, -6, and -7 all associate directly with the Sm proteins (24), and Gemin2, -3, -4, -6, and -8 and SMN are important for the U1 snRNP assembly activity of the SMN complex (20,25,26). Battle et al (27) demonstrated that Gemin5 functions as an snRNA binding protein of the SMN complex and is required for the U4 snRNP assembly activity of the SMN complex.…”

Section: Spinal Muscular Atrophy (Sma)mentioning

confidence: 99%

Gemin2 Plays an Important Role in Stabilizing the Survival of Motor Neuron Complex

Ogawa

Usui

Aoki

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The survival of motor neuron (SMN) protein, responsible for the neurodegenerative disease spinal muscular atrophy (SMA), oligomerizes and forms a stable complex with seven other major components, the Gemin proteins. Besides the SMN protein, Gemin2 is a core protein that is essential for the formation of the SMN complex, although the mechanism by which it drives formation is unclear. We have found a novel interaction, a Gemin2 self-association, using the mammalian two-hybrid system and the in vitro pull-down assays. Using in vitro dissociation assays, we also found that the self-interaction of the amino-terminal SMN protein, which was confirmed in this study, became stable in the presence of Gemin2. In addition, Gemin2 knockdown using small interference RNA treatment revealed a drastic decrease in SMN oligomer formation and in the assembly activity of spliceosomal small nuclear ribonucleoprotein (snRNP). Taken together, these results indicate that Gemin2 plays an important role in snRNP assembly through the stabilization of the SMN oligomer/complex via novel self-interaction. Applying the results/techniques to amino-terminal SMN missense mutants that were recently identified from SMA patients, we successfully showed that amino-terminal self-association, Gemin2 binding, the stabilization effect of Gemin2, and snRNP assembly activity were all lowered in the mutant SMN(D44V), suggesting that instability of the amino-terminal SMN self-association may cause SMA in patients carrying this allele. Spinal muscular atrophy (SMA)2 is a common autosomal recessive disease that is clinically classified into three types, I-III, based on the severity of motor neuron degeneration and the age of onset (1-3). Two nearly identical copies of the survival of motor neuron genes (SMN1 and SMN2) are located on the human chromosome, 5q13, whereas other eukaryotic species have only one copy of the SMN gene. Homozygous deletions of, or mutations in the SMN1 gene are responsible for SMA (4). SMN is expressed ubiquitously and is a core component of a self-assembling multiprotein complex, the SMN complex, consisting of SMN and Gemin proteins, which plays an essential role in the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs) and in pre-mRNA splicing (5, 6).Most of the missense mutations in SMA patients are located in exon 6 of SMN1; whereas nonsense and frameshift mutations are widely spread throughout the entire gene (7). Exon 6 of SMN1 encodes a self-association domain, and deletions or mutations of this domain result in a decrease in oligomer formation of SMN, which correlates with the severity of SMA (8). SMN oligomerization is also a prerequisite for high affinity binding of the SMN complex to spliceosomal snRNPs (9). The self-association domains of SMN were identified by surface plasmon resonance analysis; both the carboxyl-terminal exon 6-encoded region and the amino-terminal exon 2b-encoded region contributed to self-association (10). This suggests a mechanism in which the self-association formation involves eit...

show abstract

“…In fetal tissues and a small subset of cell lines, SMN localizes to distinct nuclear structures known as Gemini bodies (gems), so named because of their typical close proximity to CBs (6). SMN is the central member of a large macromolecular complex (7,8). Members of this so-called SMN complex are termed ''Gemins'' because they colocalize with SMN in gems and CBs.…”

mentioning

confidence: 99%

Gemin proteins are required for efficient assembly of Sm-class ribonucleoproteins

Shpargel

Matera

2005

Proc. Natl. Acad. Sci. U.S.A.

190

215

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of spinal motor neurons. The gene encoding the survival of motor neurons (SMN) protein is mutated in >95% of SMA cases. SMN is the central component of a large oligomeric complex, including Gemins2-7, that is necessary and sufficient for the in vivo assembly of Sm proteins onto the small nuclear (sn)RNAs that mediate pre-mRNA splicing. After cytoplasmic assembly of the Sm core, both SMN and splicing snRNPs are imported into the nucleus, accumulating in Cajal bodies for additional snRNA maturation steps before targeting to splicing factor compartments known as ''speckles.'' In this study, we analyzed the function of individual SMN complex members by RNA interference (RNAi). RNAi-mediated knockdown of SMN, Gemin2, Gemin3, and Gemin4 each disrupted Sm core assembly, whereas knockdown of Gemin5 and Snurportin1 had no effect. Assembly activity was rescued by expression of a GFP-SMN construct that is refractive to RNAi but not by similar constructs that contain SMA patient-derived mutations. Our results also demonstrate that Cajal body homeostasis requires SMN and ongoing snRNP biogenesis. Perturbation of SMN function results in disassembly of Cajal bodies and relocalization of the marker protein, coilin, to nucleoli. Moreover, in SMN-deficient cells, newly synthesized SmB proteins fail to associate with U2 snRNA or accumulate in Cajal bodies. Collectively, our results identify a previously uncharacterized function for Gemin3 and Gemin4 in Sm core assembly and correlate the activity of this pathway with SMA.coilin ͉ DEAD box proteins ͉ RNA helicases ͉ small nuclear ribonucleoprotein biogenesis ͉ spinal muscular atrophy

show abstract

SMN-mediated assembly of RNPs: a complex story

Cited by 211 publications

References 63 publications

Repair of pre-mRNA splicing

Repair of pre-mRNA splicing

Gemin2 Plays an Important Role in Stabilizing the Survival of Motor Neuron Complex

Gemin proteins are required for efficient assembly of Sm-class ribonucleoproteins

Contact Info

Product

Resources

About