The Survival Motor Neuron Protein Forms Soluble Glycine Zipper Oligomers

Abstract

The Survival Motor Neuron (SMN) protein forms the oligomeric core of a multi-protein complex that functions in spliceosomal snRNP biogenesis. Loss of function mutations in the SMN gene cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Nearly half of the known SMA patient missense mutations map to the SMN YG-box, a highly conserved oligomerization domain of unknown structure that contains a (YxxG)3 motif. Here we report that the SMN YG-box forms helical oligomers similar to the glycine zippers found in transmembrane channel proteins. A novel network of tyrosine-glycine packing between helices drives formation of soluble YG-box oligomers, providing a structural basis for understanding SMN oligomerization and for relating defects in oligomerization to the mutations found in SMA patients. These results have important implications for advancing our understanding of SMN function and glycine zipper-mediated helix-helix interactions.

The SMN Tudor SIM-like domain is key to SmD1 and coilin interactions and to Cajal body biogenesis

“…4E,F). These results are consistent with previous reports suggesting that the SMN motifs responsible for SMN oligomerization and Gemin2 binding are far from the Tudor domain (Martin et al, 2012).…”

“…4A): (1) SMN oligomerization (Lorson et al, 1998;Martin et al, 2012), (2) SMN interaction with Gemin proteins (Zhang et al, 2011), (3) SMN binding to the Sm complex proteins of snRNPs, which are key constituents of spliceosomes (Pellizzoni et al, 2002), and (4) SMN-coilin interaction in CBs (Hebert et al, 2001) (Fig. 4A).…”

Oligomeric Properties of Survival Motor Neuron·Gemin2 Complexes

“…The ySMN⅐Gemin2 complex forms an equilibrium mixture of dimers and tetramers but does not form higher order oligomers even at elevated concentrations. A crystal structure of the ySMN YG box reveals remarkable conservation of structure with the previously reported hSMN YG box (20) and extends that structural model in both directions from the highly conserved core sequence. We have exploited the simplicity and favorable biochemistry of the yeast system to further show that the SMN tetramer is formed by self-association of stable SMN⅐Gemin2 dimers and is not a symmetrical bundle of glycine zipper helices similar to membrane ion channels with related oligomerization motifs (21).…”

“…Structure Determination-To obtain crystals of the ySMN YG box, we used the same strategy of screening MBP-YG box fusions that proved successful in earlier work (20). Only one fusion led to diffraction quality crystals, resulting in a structural model for residues 119 -149 (residues 150 -152 are poorly ordered).…”

SMN - A chaperone for nuclear RNP social occasions?

“…101,102 The core of this helical domain contains a highly conserved YxxxYxxxY motif. 101 Notably, phylogenetic analysis reveals that this motif can be extended on both ends to form a longer LxxxLxxxYxxxYxxxYxxxL helix (A. G.M., unpublished observations).…”