Assembly of higher-order SMN oligomers is essential for metazoan viability and requires an exposed structural motif present in the YG zipper dimer

Gupta, Kushol; Wen, Ying; Ninan, Nisha S.; Raimer, Amanda C.; Sharp, Robert; Spring, Ashlyn M.; Sarachan, Kathryn L.; Johnson, Meghan C.; Van Duyne, Gregory D.; Matera, A. Gregory

doi:10.1093/nar/gkab508

Title: Assembly of higher-order SMN oligomers is essential for metazoan viability and requires an exposed structural motif present in the YG zipper dimer

Journal Article · 27 June 2021 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gkab508 · OSTI ID:1798942

Gupta, Kushol ^[1]; Wen, Ying ^[2]; Ninan, Nisha S. ^[1]; Raimer, Amanda C. ^[3]; Sharp, Robert ^[1]; Spring, Ashlyn M. ^[4]; Sarachan, Kathryn L. ^[1]; Johnson, Meghan C. ^[5]; Van Duyne, Gregory D. ^[1];

^[6]

Department of Biochemistry & Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105-6059, USA
Integrative Program for Biological & Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
Integrative Program for Biological & Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA, Curriculum in Genetics and Molecular Biology, Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
Integrative Program for Biological & Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA, Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA
Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA
Integrative Program for Biological & Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA, Curriculum in Genetics and Molecular Biology, Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA, Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA

Abstract Protein oligomerization is one mechanism by which homogenous solutions can separate into distinct liquid phases, enabling assembly of membraneless organelles. Survival Motor Neuron (SMN) is the eponymous component of a large macromolecular complex that chaperones biogenesis of eukaryotic ribonucleoproteins and localizes to distinct membraneless organelles in both the nucleus and cytoplasm. SMN forms the oligomeric core of this complex, and missense mutations within its YG box domain are known to cause Spinal Muscular Atrophy (SMA). The SMN YG box utilizes a unique variant of the glycine zipper motif to form dimers, but the mechanism of higher-order oligomerization remains unknown. Here, we use a combination of molecular genetic, phylogenetic, biophysical, biochemical and computational approaches to show that formation of higher-order SMN oligomers depends on a set of YG box residues that are not involved in dimerization. Mutation of key residues within this new structural motif restricts assembly of SMN to dimers and causes locomotor dysfunction and viability defects in animal models.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: SC0012704

OSTI ID:: 1798942

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 13 Vol. 49; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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