The Gemin2 Complex: An Evolving View Of Smn Mediated Snrnp Assembly

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Doctor of Philosophy (PhD)
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Biochemistry & Molecular Biophysics
Molecular Biology
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Assembly of spliceosome snRNPs requires a megadalton molecular machine called the survival of motor neuron (SMN) complex. In higher eukaryotes, this complex consists of SMN, Gemins2-8 and unrip. Deficiency in SMN causes spinal muscular atrophy (SMA), a leading cause of heritable mortality in infants and children. The mechanism of precisely how seven Sm proteins are arranged in a ring around an snRNA, to form a snRNP was not well understood, due in part to the large number of components and heterogeneity of the SMN complex. Through use of several techniques including: RNA gel-shifts, pull-downs, Förster resonance energy transfer, ultracentrifugation, electron microscopy, molecular modeling and genetic manipulation in simple model organisms and human cells, this area was illuminated. Here I will present evidence for Sm5 dependent association of Gemin2 with SMN. Through a series of hydrophobic interactions between amino and carboxy termini, binding of Sm protein to Gemin2 opens a binding site for SMN on its distal side, in both human and S. pombe. I will prove that human SMN complexes in cells require Gemin8 to form large oligomers. I will demonstrate that the oligomerization state of S. pombe SMN is a tetramer, and visualize its complete SMN complex. I will show that both S. pombe and S. cerevisiae SMN-Gemin2 and Brr1 are sufficient for snRNP assembly from recombinant sources. I will further show that S. cerevisiae Brr1 is capable of binding all substrates of the SMN complex. Through genetics I demonstrate a toxicity from Gemin2, when its levels exceed SMN capacity in S. pombe. Finally, I will suggest that the imbalance of Gemin2 and SMN occurs in the devastating childhood disease, SMA, and is a contributing factor. These results amount to a paradigm shift wherein Gemin2 usurps SMN as the most important member of the now SMN-Gemin2 complex for snRNP. Furthermore, with toxicity of excess Gemin2 relative to SMN and the likelihood of this occurring in SMA patients, Gemin2’s position of importance as a potential therapeutic target in SMA has been revealed.

Gideon Dreyfuss
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