Structural Basis of the Disorder in the Tandem Zinc Finger Domain of the RNA-Binding Protein Tristetraprolin

An emerging theme in cellular logistics is the close connection between mRNA and membrane trafficking. A prominent example is the microtubule-dependent transport of mRNAs and associated ribosomes on endosomes. This coordinated process is crucial for correct septin filamentation and efficient growth of polarised cells, such as fungal hyphae. Despite detailed knowledge on the key RNA-binding protein and the molecular motors involved, it is unclear how mRNAs are connected to membranes during transport. Here, we identify a novel factor containing a FYVE zinc finger domain for interaction with endosomal lipids and a new PAM2-like domain required for interaction with the MLLE domain of the key RNA-binding protein. Consistently, loss of this FYVE domain protein leads to specific defects in mRNA, ribosome, and septin transport without affecting general functions of endosomes or their movement. Hence, this is the first endosomal component specific for mRNP trafficking uncovering a new mechanism to couple mRNPs to endosomes.

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Faculty Opinions recommendation of Cold-inducible zinc finger-containing glycine-rich RNA-binding protein contributes to the enhancement of freezing tolerance in Arabidopsis thaliana.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1026431.323264 ◽

2005 ◽

Author(s):

Michael Thomashow

Keyword(s):

Arabidopsis Thaliana ◽

Zinc Finger ◽

Freezing Tolerance ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein

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Structural basis of nucleic acid binding byNicotiana tabacumglycine-rich RNA-binding protein: implications for its RNA chaperone function

Nucleic Acids Research ◽

10.1093/nar/gku468 ◽

2014 ◽

Vol 42 (13) ◽

pp. 8705-8718 ◽

Cited By ~ 12

Author(s):

Fariha Khan ◽

Mark A. Daniëls ◽

Gert E. Folkers ◽

Rolf Boelens ◽

S. M. Saqlan Naqvi ◽

...

Keyword(s):

Nucleic Acid ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Structural Basis ◽

Nucleic Acid Binding ◽

Rna Chaperone ◽

Chaperone Function

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Structural basis of the zinc-induced cytoplasmic aggregation of the RNA-binding protein SFPQ

Nucleic Acids Research ◽

10.1093/nar/gkaa076 ◽

2020 ◽

Vol 48 (6) ◽

pp. 3356-3365 ◽

Cited By ~ 4

Author(s):

Jie Huang ◽

Mitchell Ringuet ◽

Andrew E Whitten ◽

Sofia Caria ◽

Yee Wa Lim ◽

...

Keyword(s):

Crystal Structure ◽

Cortical Neurons ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Zinc Binding ◽

Structural Basis ◽

Rna Biogenesis ◽

Cytoplasmic Accumulation ◽

Nucleocytoplasmic Distribution

Abstract SFPQ is a ubiquitous nuclear RNA-binding protein implicated in many aspects of RNA biogenesis. Importantly, nuclear depletion and cytoplasmic accumulation of SFPQ has been linked to neuropathological conditions such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Here, we describe a molecular mechanism by which SFPQ is mislocalized to the cytoplasm. We report an unexpected discovery of the infinite polymerization of SFPQ that is induced by zinc binding to the protein. The crystal structure of human SFPQ in complex with zinc at 1.94 Å resolution reveals intermolecular interactions between SFPQ molecules that are mediated by zinc. As anticipated from the crystal structure, the application of zinc to primary cortical neurons induced the cytoplasmic accumulation and aggregation of SFPQ. Mutagenesis of the three zinc-coordinating histidine residues resulted in a significant reduction in the zinc-binding affinity of SFPQ in solution and the zinc-induced cytoplasmic aggregation of SFPQ in cultured neurons. Taken together, we propose that dysregulation of zinc availability and/or localization in neuronal cells may represent a mechanism for the imbalance in the nucleocytoplasmic distribution of SFPQ, which is an emerging hallmark of neurodegenerative diseases including AD and ALS.

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Structural basis underlying CAC RNA recognition by the RRM domain of dimeric RNA-binding protein RBPMS

Quarterly Reviews of Biophysics ◽

10.1017/s0033583515000207 ◽

2015 ◽

Vol 49 ◽

Cited By ~ 21

Author(s):

Marianna Teplova ◽

Thalia A. Farazi ◽

Thomas Tuschl ◽

Dinshaw J. Patel

Keyword(s):

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Hek293 Cells ◽

Structural Basis ◽

Rna Recognition Motif ◽

Rna Recognition ◽

Binding Studies ◽

Muscle Plasticity ◽

Rrm Domain

AbstractRNA-binding protein with multiple splicing (designated RBPMS) is a higher vertebrate mRNA-binding protein containing a single RNA recognition motif (RRM). RBPMS has been shown to be involved in mRNA transport, localization and stability, with key roles in axon guidance, smooth muscle plasticity, as well as regulation of cancer cell proliferation and migration. We report on structure-function studies of the RRM domain of RBPMS bound to a CAC-containing single-stranded RNA. These results provide insights into potential topologies of complexes formed by the RBPMS RRM domain and the tandem CAC repeat binding sites as detected by photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation. These studies establish that the RRM domain of RBPMS forms a symmetrical dimer in the free state, with each monomer binding sequence-specifically to all three nucleotides of a CAC segment in the RNA bound state. Structure-guided mutations within the dimerization and RNA-binding interfaces of RBPMS RRM on RNA complex formation resulted in both disruption of dimerization and a decrease in RNA-binding affinity as observed by size exclusion chromatography and isothermal titration calorimetry. As anticipated from biochemical binding studies, over-expression of dimerization or RNA-binding mutants of Flag-HA-tagged RBPMS were no longer able to track with stress granules in HEK293 cells, thereby documenting the deleterious effects of such mutations in vivo.

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