Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q16637 (SMA)
 8,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The assembly of the Sm-class of uridine-rich small nuclear ribonucleoproteins (U snRNPs), albeit spontaneous in vitro, has recently been shown to be dependent on the aid of a large number of assisting factors in vivo. These factors are organized in two interacting units termed survival motor neuron (SMN)- and protein arginine methyltransferase 5 (PRMT5)-complexes, respectively. While the PRMT5-complex acts early in the assembly pathway by activating common proteins of U snRNPs, the SMN-complex functions to join proteins and RNA in a highly ordered, apparently regulated manner. Here, we summarize recent progress in the understanding of this process and discuss the influence exerted by the aforementioned trans-acting factors.
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PMID:Deciphering the assembly pathway of Sm-class U snRNPs. 1834 70

Specialized assembly factors facilitate the formation of many macromolecular complexes in vivo. The formation of Sm core structures of spliceosomal U-rich small nuclear ribonucleoprotein particles (UsnRNPs) requires assembly factors united in protein arginine methyltransferase 5 (PRMT5) and survival motor neuron (SMN) complexes. We demonstrate that perturbations of this assembly machinery trigger complex cellular responses that prevent aggregation of unassembled Sm proteins. Inactivation of the SMN complex results in the initial tailback of Sm proteins on the PRMT5 complex, followed by down-regulation of their encoding mRNAs. In contrast, reduction of pICln, a PRMT5 complex subunit, leads to the retention of newly synthesized Sm proteins on ribosomes and their subsequent lysosomal degradation. Overexpression of Sm proteins under these conditions results in a surplus of Sm proteins over pICln, promoting their aggregation. Our studies identify an elaborate safeguarding system that prevents individual Sm proteins from aggregating, contributing to cellular UsnRNP homeostasis.
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PMID:Impaired spliceosomal UsnRNP assembly leads to Sm mRNA down-regulation and Sm protein degradation. 2863 48

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2-8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a "housekeeping" activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.
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PMID:Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction. 2864 65

Macromolecular complexes composed of proteins or proteins and nucleic acids rather than individual macromolecules mediate many cellular activities. Maintenance of these activities is essential for cell viability and requires the coordinated production of the individual complex components as well as their faithful incorporation into functional entities. Failure of complex assembly may have fatal consequences and can cause severe diseases. While many macromolecular complexes can form spontaneously in vitro, they often require aid from assembly factors including assembly chaperones in the crowded cellular environment. The assembly of RNA protein complexes implicated in the maturation of pre-mRNAs (termed UsnRNPs) has proven to be a paradigm to understand the action of assembly factors and chaperones. UsnRNPs are assembled by factors united in protein arginine methyltransferase 5 (PRMT5)- and survival motor neuron (SMN)-complexes, which act sequentially in the UsnRNP production line. While the PRMT5-complex pre-arranges specific sets of proteins into stable intermediates, the SMN complex displaces assembly factors from these intermediates and unites them with UsnRNA to form the assembled RNP. Despite advanced mechanistic understanding of UsnRNP assembly, our knowledge of regulatory features of this essential and ubiquitous cellular function remains remarkably incomplete. One may argue that the process operates as a default biosynthesis pathway and does not require sophisticated regulatory cues. Simple theoretical considerations and a number of experimental data, however, indicate that regulation of UsnRNP assembly most likely happens at multiple levels. This review will not only summarize how individual components of this assembly line act mechanistically but also why, how, and when the UsnRNP workflow might be regulated by means of posttranslational modification in response to cellular signaling cues.
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PMID:UsnRNP biogenesis: mechanisms and regulation. 2876 49