RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules

Sci Rep. 2015 Sep 22;5:14262. doi: 10.1038/srep14262.

Abstract

The aggregation of RNA-binding proteins is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RBM45 is an RNA-binding protein that forms cytoplasmic inclusions in neurons and glia in ALS and FTLD. To explore the role of RBM45 in ALS and FTLD, we examined the contribution of the protein's domains to its function, subcellular localization, and interaction with itself and ALS-linked proteins. We find that RBM45 forms homo-oligomers and physically associates with the ALS-linked proteins TDP-43 and FUS in the nucleus. Nuclear localization of RBM45 is mediated by a bipartite nuclear-localization sequence (NLS) located at the C-terminus. RBM45 mutants that lack a functional NLS accumulate in the cytoplasm and form TDP-43 positive stress granules. Moreover, we identify a novel structural element, termed the homo-oligomer assembly (HOA) domain, that is highly conserved across species and promote homo-oligomerization of RBM45. RBM45 mutants that fail to form homo-oligomers exhibit significantly reduced association with ALS-linked proteins and inclusion into stress granules. These results show that RMB45 may function as a homo-oligomer and that its oligomerization contributes to ALS/FTLD RNA-binding protein aggregation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Carrier Proteins / metabolism*
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Humans
  • Inclusion Bodies / metabolism*
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Localization Signals / chemistry
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs / genetics
  • Protein Interaction Maps
  • Protein Multimerization*
  • Protein Transport
  • RNA-Binding Protein FUS / metabolism
  • RNA-Binding Proteins / chemistry*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Sequence Alignment

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • Nuclear Localization Signals
  • RBM45 protein, human
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins