scholarly journals Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins

2000 ◽  
Vol 9 (13) ◽  
pp. 1977-1986 ◽  
Author(s):  
G. Meister
Keyword(s):  
Motor Neurons ◽  
Sm Proteins ◽  
Specific Subset ◽  
Survival Of Motor Neurons ◽  
Smn Protein

scholarly journals The SMN Complex Is Associated with snRNPs throughout Their Cytoplasmic Assembly Pathway

2002 ◽  
Vol 22 (18) ◽  
pp. 6533-6541 ◽  
Author(s):  
Séverine Massenet ◽  
Livio Pellizzoni ◽  
Sergey Paushkin ◽  
Iain W. Mattaj ◽  
Gideon Dreyfuss
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Sm Proteins ◽  
Assembly Pathway ◽  
Smn Complex ◽  
Complex Functions ◽  
Survival Of Motor Neurons ◽  
The Common ◽  
Smn Protein ◽  
Cytoplasmic Assembly

ABSTRACT The common neurodegenerative disease spinal muscular atrophy is caused by reduced levels of the survival of motor neurons (SMN) protein. SMN associates with several proteins (Gemin2 to Gemin6) to form a large complex which is found both in the cytoplasm and in the nucleus. The SMN complex functions in the assembly and metabolism of several RNPs, including spliceosomal snRNPs. The snRNP core assembly takes place in the cytoplasm from Sm proteins and newly exported snRNAs. Here, we identify three distinct cytoplasmic SMN complexes, each representing a defined intermediate in the snRNP biogenesis pathway. We show that the SMN complex associates with newly exported snRNAs containing the nonphosphorylated form of the snRNA export factor PHAX. The second SMN complex identified contains assembled Sm cores and m3G-capped snRNAs. Finally, the SMN complex is associated with a preimport complex containing m3G-capped snRNP cores bound to the snRNP nuclear import mediator snurportin1. Thus, the SMN complex is associated with snRNPs during the entire process of their biogenesis in the cytoplasm and may have multiple functions throughout this process.

Small nuclear RNAs and mRNAs: linking RNA processing and transport to spinal muscular atrophy

2013 ◽  
Vol 41 (4) ◽  
pp. 871-875 ◽  
Author(s):  
Judith Sleeman
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Early Stage ◽  
Cell Type Specificity ◽  
Sm Proteins ◽  
Spinal Motor Neurons ◽  
Survival Of Motor Neurons ◽  
Smn Protein ◽  
Multicellular Organisms

The splicing of pre-mRNA by the spliceosome is a characteristic feature of eukaryotic cells, dependent on a group of snRNPs (small nuclear ribonucleoproteins). These splicing snRNPs have a complex assembly pathway involving multiple steps that take place in different regions of the cell, which is reflected in their complex subcellular distribution. Vital to the assembly of splicing snRNPs is the protein SMN (survival of motor neurons). In multicellular organisms, SMN acts in the cytoplasm, together with its associated protein complex to assemble a heptameric ring of proteins called the Sm proteins as an early stage in splicing snRNP assembly. A deficiency of the SMN protein results in the inherited neurodegenerative condition SMA (spinal muscular atrophy), a leading cause of infant mortality specifically affecting spinal motor neurons. It has long been a puzzle how lowered levels of a protein required for a process as fundamental as splicing snRNP assembly can result in a condition with such a definite cell-type-specificity. The present review highlights recent research that points to wider roles in RNA metabolism for both SMN itself and the Sm proteins with which it is linked.

scholarly journals The Survival of Motor Neurons Protein Determines the Capacity for snRNP Assembly: Biochemical Deficiency in Spinal Muscular Atrophy

2005 ◽  
Vol 25 (13) ◽  
pp. 5543-5551 ◽  
Author(s):  
Lili Wan ◽  
Daniel J. Battle ◽  
Jeongsik Yong ◽  
Amelie K. Gubitz ◽  
Stephen J. Kolb ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Protein Levels ◽  
Small Nuclear Ribonucleoprotein ◽  
Cell Extracts ◽  
Smn Complex ◽  
Survival Of Motor Neurons ◽  
Smn Protein ◽  
Nuclear Ribonucleoprotein

ABSTRACT Reduction of the survival of motor neurons (SMN) protein levels causes the motor neuron degenerative disease spinal muscular atrophy, the severity of which correlates with the extent of reduction in SMN. SMN, together with Gemins 2 to 7, forms a complex that functions in the assembly of small nuclear ribonucleoprotein particles (snRNPs). Complete depletion of the SMN complex from cell extracts abolishes snRNP assembly, the formation of heptameric Sm cores on snRNAs. However, what effect, if any, reduction of SMN protein levels, as occurs in spinal muscular atrophy patients, has on the capacity of cells to produce snRNPs is not known. To address this, we developed a sensitive and quantitative assay for snRNP assembly, the formation of high-salt- and heparin-resistant stable Sm cores, that is strictly dependent on the SMN complex. We show that the extent of Sm core assembly is directly proportional to the amount of SMN protein in cell extracts. Consistent with this, pulse-labeling experiments demonstrate a significant reduction in the rate of snRNP biogenesis in low-SMN cells. Furthermore, extracts of cells from spinal muscular atrophy patients have a lower capacity for snRNP assembly that corresponds directly to the reduced amount of SMN. Thus, SMN determines the capacity for snRNP biogenesis, and our findings provide evidence for a measurable deficiency in a biochemical activity in cells from patients with spinal muscular atrophy.

SMN complexes of nucleus and cytoplasm: A proteomic study for SMA therapy

2010 ◽  
Vol 1 (4) ◽  
Author(s):  
Heidi Fuller ◽  
Glenn Morris
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Ubiquitin Proteasome System ◽  
Neuromuscular Disorder ◽  
Nuclear Extracts ◽  
Smn Complex ◽  
Proteomic Study ◽  
Ubiquitin Proteasome ◽  
Survival Of Motor Neurons ◽  
Smn Protein

AbstractReduced levels of the survival of motor neurons protein (SMN), cause the inherited neuromuscular disorder, spinal muscular atrophy (SMA). The majority of therapeutic approaches to date have been focused on finding ways to increase expression of functional SMN protein, though stabilization of SMN protein may also be an important consideration. SMN interacts, directly or indirectly, stably or transiently, with a large number of other proteins, some of which contribute to SMN stability and may therefore be potential targets for SMA therapy. We recently characterized the nuclear SMN interactome using LC-MALDI-TOF/TOF analysis of anti-SMN pull-downs and identified myb-binding protein-1a (Mybbp1a) as a novel partner. In light of interest in cytoplasm-specific roles of the SMN complex, we have applied the same approach to characterise the cytoplasmic SMN interactome. We now show that SMN complexes from HeLa cytoplasmic extracts differ significantly from those found in nuclear extracts, with gemin5, importinbeta and annexin A2 easily detected only in the cytoplasmic extracts, whereas interaction of SMN with Mybbp1a appears to occur only in the nucleus. SMN is ubiquitinylated and we also found proteins of the ubiquitin-proteasome system associated with SMN in the cytoplasm.

scholarly journals Lymphotropic Herpesvirus saimiri Uses the SMN Complex To Assemble Sm Cores on Its Small RNAs

2005 ◽  
Vol 25 (2) ◽  
pp. 602-611 ◽  
Author(s):  
Tracey J. Golembe ◽  
Jeongsik Yong ◽  
Daniel J. Battle ◽  
Wenqin Feng ◽  
Lili Wan ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Small Rnas ◽  
Herpesvirus Saimiri ◽  
New World Monkeys ◽  
Infectious Agents ◽  
Sm Proteins ◽  
General Utility ◽  
Smn Complex ◽  
Survival Of Motor Neurons ◽  
Very High

ABSTRACT The lymphotropic Herpesvirus saimiri (HVS) causes acute leukemia, T-cell lymphoma, and death in New World monkeys. HVS encodes seven small RNAs (HSURs) of unknown function. The HSURs acquire host Sm proteins and assemble Sm cores similar to those found on the spliceosomal small nuclear RNPs (snRNPs). Here we show that, like host snRNPs, HSURs use the SMN (survival of motor neurons) complex to assemble Sm cores. The HSURs bind the SMN complex directly and with very high affinity, similar to or higher than that of host snRNAs, and can outcompete host snRNAs for SMN-dependent assembly into RNPs. These observations highlight the general utility of the SMN complex for RNP assembly and suggest that infectious agents that engage the SMN complex may burden SMN-dependent pathways, possibly leading to a deleterious reduction in available SMN complex for essential host functions.

scholarly journals Cross-Talk between Snurportin1 Subdomains

2005 ◽  
Vol 16 (10) ◽  
pp. 4660-4671 ◽  
Author(s):  
Jason K. Ospina ◽  
Graydon B. Gonsalvez ◽  
Janna Bednenko ◽  
Edward Darzynkiewicz ◽  
Larry Gerace ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Protein Complexes ◽  
Cajal Bodies ◽  
Leptomycin B ◽  
Small Nuclear Ribonucleoprotein ◽  
Tryptophan Residues ◽  
Importin Α ◽  
Survival Of Motor Neurons ◽  
Smn Protein ◽  
Nuclear Ribonucleoprotein

The initial steps of spliceosomal small nuclear ribonucleoprotein (snRNP) maturation take place in the cytoplasm. After formation of an Sm-core and a trimethylguanosine (TMG) cap, the RNPs are transported into the nucleus via the import adaptor snurportin1 (SPN) and the import receptor importin-β. To better understand this process, we identified SPN residues that are required to mediate interactions with TMG caps, importin-β, and the export receptor, exportin1 (Xpo1/Crm1). Mutation of a single arginine residue within the importin-β binding domain (IBB) disrupted the interaction with importin-β, but preserved the ability of SPN to bind Xpo1 or TMG caps. Nuclear transport assays showed that this IBB mutant is deficient for snRNP import but that import can be rescued by addition of purified survival of motor neurons (SMN) protein complexes. Conserved tryptophan residues outside of the IBB are required for TMG binding. However, SPN can be imported into the nucleus without cargo. Interestingly, SPN targets to Cajal bodies when U2 but not U1 snRNPs are imported as cargo. SPN also relocalizes to Cajal bodies upon treatment with leptomycin B. Finally, we uncovered an interaction between the N- and C-terminal domains of SPN, suggesting an autoregulatory function similar to that of importin-α.

scholarly journals The survival of motor neurons (SMN) protein interacts with the snoRNP proteins fibrillarin and GAR1

2001 ◽  
Vol 11 (14) ◽  
pp. 1079-1088 ◽  
Author(s):  
Livio Pellizzoni ◽  
Jennifer Baccon ◽  
Bernard Charroux ◽  
Gideon Dreyfuss
Keyword(s):  
Motor Neurons ◽  
Survival Of Motor Neurons ◽  
Smn Protein

scholarly journals snRNAs Contain Specific SMN-Binding Domains That Are Essential for snRNP Assembly

2004 ◽  
Vol 24 (7) ◽  
pp. 2747-2756 ◽  
Author(s):  
Jeongsik Yong ◽  
Tracey J. Golembe ◽  
Daniel J. Battle ◽  
Livio Pellizzoni ◽  
Gideon Dreyfuss
Keyword(s):  
Motor Neurons ◽  
Sequence Similarity ◽  
Structural Features ◽  
Sm Proteins ◽  
Specific Domain ◽  
Stem Loop ◽  
Binding Domains ◽  
Small Nuclear Ribonucleoprotein ◽  
Smn Complex ◽  
Smn Protein

ABSTRACT To serve in its function as an assembly machine for spliceosomal small nuclear ribonucleoprotein particles (snRNPs), the survival of motor neurons (SMN) protein complex binds directly to the Sm proteins and the U snRNAs. A specific domain unique to U1 snRNA, stem-loop 1 (SL1), is required for SMN complex binding and U1 snRNP Sm core assembly. Here, we show that each of the major spliceosomal U snRNAs (U2, U4, and U5), as well as the minor splicing pathway U11 snRNA, contains a domain to which the SMN complex binds directly and with remarkable affinity (low nanomolar concentration). The SMN-binding domains of the U snRNAs do not have any significant nucleotide sequence similarity yet they compete for binding to the SMN complex in a manner that suggests the presence of at least two binding sites. Furthermore, the SMN complex-binding domain and the Sm site are both necessary and sufficient for Sm core assembly and their relative positions are critical for snRNP assembly. These findings indicate that the SMN complex stringently scrutinizes RNAs for specific structural features that are not obvious from the sequence of the RNAs but are required for their identification as bona fide snRNAs. It is likely that this surveillance capacity of the SMN complex ensures assembly of Sm cores on the correct RNAs only and prevents illicit, potentially deleterious, assembly of Sm cores on random RNAs.

A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells

2005 ◽  
Vol 309 (1) ◽  
pp. 185-197 ◽  
Author(s):  
Aarti Sharma ◽  
Anja Lambrechts ◽  
Le thi Hao ◽  
Thanh T. Le ◽  
Caroline A. Sewry ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Nerve Cells ◽  
Survival Of Motor Neurons ◽  
Smn Protein ◽  
Cultured Nerve Cells

scholarly journals Specific Sequence Features, Recognized by the SMN Complex, Identify snRNAs and Determine Their Fate as snRNPs

2005 ◽  
Vol 25 (24) ◽  
pp. 10989-11004 ◽  
Author(s):  
Tracey J. Golembe ◽  
Jeongsik Yong ◽  
Gideon Dreyfuss
Keyword(s):  
Motor Neurons ◽  
Structural Features ◽  
Base Pairs ◽  
Sm Proteins ◽  
Specific Sequence ◽  
Stem Loop ◽  
Smn Complex ◽  
Small Nuclear Rnas ◽  
Survival Of Motor Neurons ◽  
Small Nuclear Ribonucleoproteins

ABSTRACT The survival of motor neurons (SMN) complex is essential for the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs) as it binds to and delivers Sm proteins for assembly of Sm cores on the abundant small nuclear RNAs (snRNAs). Using the conserved snRNAs encoded by the lymphotropic Herpesvirus saimiri (HVS), we determined the specific sequence and structural features of RNAs for binding to the SMN complex and for Sm core assembly. We show that the minimal SMN complex-binding domain in snRNAs, except U1, is comprised of an Sm site (AUUUUUG) and an adjacent 3′ stem-loop. The adenosine and the first and third uridines of the Sm site are particularly critical for binding of the SMN complex, which directly contacts the backbone phosphates of these uridines. The specific sequence of the adjacent stem (7 to 12 base pairs)-loop (4 to 17 nucleotides) is not important for SMN complex binding, but it must be located within a short distance of the 3′ end of the RNA for an Sm core to assemble. Importantly, these defining characteristics are discerned by the SMN complex and not by the Sm proteins, which can bind to and assemble on an Sm site sequence alone. These findings demonstrate that the SMN complex is the identifier, as well as assembler, of the abundant class of snRNAs in cells because it is able to recognize an snRNP code that they contain.

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