R1 Motif is the Major Actin Binding Domain of TRIOBP-4

Bao, Jianjun; Bielski, Elizabeth; Bachhawat, Ankita; Thirumurugan, Kavitha; Sakamoto, Takeshi

doi:10.1016/j.bpj.2012.11.3574

Cited by 3 publications

(9 citation statements)

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“…That the central and C-terminal domains are each capable of modulating actin dynamics in isolation is analogous to the fact that both the TRIOBP-1 and TRIOBP-4 proteins modulate actin despite sharing no common amino acid sequence. It thus appears that longer isoforms of TRIOBP, such as TRIOBP-6, could contain at least three distinct actin-binding and -modulating domains: the central and C-terminal regions of TRIOBP-1 plus the R1 motif of TRIOBP-4 (5).…”

Section: Triobp-1 Domain Structure and Aggregationmentioning

confidence: 99%

“…The TRIOBP 4 (Trio-binding protein) gene encodes for two distinct proteins (1,2), both of which are implicated in the modulation of actin, although the exact mechanisms by which they do this remain unclear (3,4). Of these TRIOBP-4, encoded by the 5Ј end of the gene, is a largely disordered protein (5) expressed principally in the inner ear, with mutant forms implicated in deafness (1,2,4), whereas the 3Ј-encoded TRIOBP-1 protein is predicted to be folded (3) and is more ubiquitously expressed (1,2). The TRIOBP-1 protein is also known as Tara (Trio-associated repeat on actin).…”

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confidence: 99%

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An unpredicted aggregation-critical region of the actin-polymerizing protein TRIOBP-1/Tara, determined by elucidation of its domain structure

Bradshaw¹,

Yerabham²,

Marreiros³

et al. 2017

Journal of Biological Chemistry

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Aggregation of specific proteins in the brains of patients with chronic mental illness as a result of disruptions in proteostasis is an emerging theme in the study of schizophrenia in particular. Proteins including DISC1 (disrupted in schizophrenia 1) and dysbindin-1B are found in insoluble forms within brain homogenates from such patients. We recently identified TRIOBP-1 (Trio-binding protein 1, also known as Tara) to be another such protein through an epitope discovery and proteomics approach by comparing post-mortem brain material from schizophrenia patients and control individuals. We hypothesized that this was likely to occur as a result of a specific subcellular process and that it, therefore, should be possible to identify a region of the TRIOBP-1 protein that is essential for its aggregation to occur. Here, we probe the domain organization of TRIOBP-1, finding it to possess two distinct coiled-coil domains: the central and C-terminal domains. The central domain inhibits the depolymerization of F-actin and is also responsible for oligomerization of TRIOBP-1. Along with an N-terminal pleckstrin homology domain, the central domain affects neurite outgrowth. In neuroblastoma cells it was found that the aggregation propensity of TRIOBP-1 arises from its central domain, with a short "linker" region narrowed to within amino acids 324-348, between its first two coiled coils, as essential for the formation of TRIOBP-1 aggregates. TRIOBP-1 aggregation, therefore, appears to occur through one or more specific cellular mechanisms, which therefore have the potential to be of physiological relevance for the biological process underlying the development of chronic mental illness.

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Section: Triobp-1 Domain Structure and Aggregationmentioning

confidence: 99%

mentioning

confidence: 99%

An unpredicted aggregation-critical region of the actin-polymerizing protein TRIOBP-1/Tara, determined by elucidation of its domain structure

Bradshaw¹,

Yerabham²,

Marreiros³

et al. 2017

Journal of Biological Chemistry

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“…Functional studies indicated that deletion of both repeat motifs R1 and R2 results in complete disruption of both actin-binding and bundling activities, while deletion of the R2 motif alone retains the F-actin bundling ability as well as the localization of TRIOBP to the cellular actin cytoskeleton in the stereocilia rootlets (Bao et al, 2013). Since DFNB28 is a recessive condition, it would imply that a single intact R1 motif would be sufficient for normal hearing.…”

Section: Analysis Of the Location Of Published Variants In Relation T...mentioning

confidence: 99%

“…In TRIOBP-5, the repeat motifs R1 and R2 encoded by exon 7 are essential for actin binding (Bao et al, 2013). Deletion of both R1 and R2 abolishes actin-binding and bundling by TRIOBP-4 and -5 entirely (Bao et al, 2013). Deletion of motif R2 alone retained F-actin bundling and TRIOBP localization to the cellular actin cytoskeleton, whereas R1-deficient TRIOBP-4 and TRIOBP-5 did not colocalize to actin filaments and formed thin F-actin bundles.…”

Section: Introductionmentioning

confidence: 99%

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Elucidation of repeat motifs R1‐ and R2‐related TRIOBP variants in autosomal recessive nonsyndromic hearing loss DFNB28 among indigenous South African individuals

Kabahuma

Schubert

Labuschagne³

et al. 2022

Molec Gen & Gen Med

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Background DFNB28, a recessively inherited nonsyndromic form of deafness in humans, is caused by mutations in the TRIOBP gene (MIM #609761) on chromosome 22q13. Its protein TRIOBP helps to tightly bundle F‐actin filaments, forming a rootlet that penetrates through the cuticular plate into the cochlear hair cell body. Repeat motifs R1 and R2, located in exon 7 of the TRIOBP‐5 isoform, are the actin‐binding domains. Deletion of both repeat motifs R1 and R2 results in complete disruption of both actin‐binding and bundling activities, whereas deletion of the R2 motif alone retains F‐actin bundling ability in stereocilia rootlets. Methods Target sequencing, using a custom capture panel of 180 known and candidate genes associated with sensorineural hearing loss, bioinformatics processing, and data analysis were performed. Genesis 2.0 was used for variant filtering based on quality/score read depth and minor allele frequency (MAF) thresholds of 0.005 for recessive NSHL, as reported in population‐based sequencing databases. All variants were reclassified based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines together with other variant interpretation guidelines for genetic hearing loss . Candidate variants were confirmed via Sanger sequencing according to standard protocols, using the ABIPRISM 3730 DNA Analyzer. DNA sequence analysis was performed with DNASTAR Lasergene software. Results Candidate TRIOBP variants identified among 94 indigenous sub‐Saharan African individuals were characterized through segregation analysis. Family TS005 carrying variants c.572delC, p.Pro191Argfs*50, and c.3510_3513dupTGCA, p.Pro1172Cysfs*13, demonstrated perfect cosegregation with the deafness phenotype. On the other hand, variants c.505C > A p.Asp168Glu and c.3636 T > A p.Leu1212Gln in the same family did not segregate with deafness and we have classified these variants as benign. A control family, TS067, carrying variants c.2532G > T p.Leu844Arg, c.2590C > A p.Asn867Lys, c.3484C > T p.Pro1161Leu, and c.3621 T > C p.Phe1187Leu demonstrated no cosegregation allowing us to classify these variants as benign. Together with published TRIOBP variants, the results showed that genotypes combining two truncating TRIOBP variants affecting repeat motifs R1 and R2 or R2 alone lead to a deafness phenotype, while a truncating variant affecting repeat motifs R1 and R2 or R2 alone combined with a missense variant does not. Homozygous truncating variants affecting repeat motif R2 cosegregate with the deafness phenotype. Conclusion While a single intact R1 motif may be adequate for actin‐binding and bundling in the stereocilia of cochlear hair cells, our findings indicate that a truncated R2 motif in cis seems to be incompatible with normal hearing, either by interfering with the function of an intact R1 motif or through another as yet unknown mechanism. Our study also suggests that most heterozygous missense variants involving exon 7 are likely to be tolerated.

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A novel mutation in TRIOBP gene leading to congenital deafness in a Chinese family

Zhou

Wang

et al. 2020

BMC Med Genet

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Background The autosomal recessive non-syndromic deafness DFNB28 is characterized by prelingual sensorineural hearing loss. The disease is related with mutations in TRIOBP (Trio- and F-actin-Binding Protein) gene, which has three transcripts referred to as TRIOBP-5, TRIOBP − 4 and TRIOBP-1. Among them, TRIOBP-5/− 4 are expressed in the inner ears and crucial for maintaining the structure and function of the stereocilia. Methods The proband is a 26-year-old Chinese female. She and her younger brother have being suffered from severe deafness since birth, whereas her parents, who are cousins, have normal communication ability. Hearing impairment of the two siblings was determined by pure tone audiometry. Whole Exome Sequencing (WES) was performed on the genomic DNA of the proband and Sanger sequencing was conducted on the DNA samples of the four family members. Results Tests of pure tone hearing thresholds showed a severe to profound symmetric hearing loss for the proband and her younger brother. Moreover, a novel TRIOBP c.1342C > T (p.Arg448*) variant was identified by WES in the DNA sample of the proband and confirmed by Sanger sequencing in DNA of the family members. Conclusions The TRIOBP c.1342C > T (p.Arg448*) variant is predicted to disrupt TRIOBP-5 and TRIOBP-4, which may lead to the congenital deafness. The results will broaden the spectrum of pathogenic variants in TRIOBP gene. The characteristics of deafness in the family imply that marriage between close relatives should be avoided.

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R1 Motif is the Major Actin Binding Domain of TRIOBP-4

Cited by 3 publications

References 0 publications

An unpredicted aggregation-critical region of the actin-polymerizing protein TRIOBP-1/Tara, determined by elucidation of its domain structure

An unpredicted aggregation-critical region of the actin-polymerizing protein TRIOBP-1/Tara, determined by elucidation of its domain structure

Elucidation of repeat motifs R1‐ and R2‐related TRIOBP variants in autosomal recessive nonsyndromic hearing loss DFNB28 among indigenous South African individuals

A novel mutation in TRIOBP gene leading to congenital deafness in a Chinese family

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