| 1. |
- James, John R., et al.
(författare)
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The T Cell Receptor Triggering Apparatus Is Composed of Monovalent or Monomeric Proteins
- 2011
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology, Inc.. - 0021-9258 .- 1083-351X. ; 286:37, s. 31993-32001
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the component stoichiometry of the T cell antigen receptor (TCR) triggering apparatus is essential for building realistic models of signal initiation. Recent studies suggesting that the TCR and other signaling-associated proteins are preclustered on resting T cells relied on measurements of the behavior of membrane proteins at interfaces with functionalized glass surfaces. Using fluorescence recovery after photo-bleaching, we show that, compared with the apical surface, the mobility of TCRs is significantly reduced at Jurkat T cell/glass interfaces, in a signaling-sensitive manner. Using two biophysical approaches that mitigate these effects, bioluminescence resonance energy transfer and two-color coincidence detection microscopy, we show that, within the uncertainty of the methods, the membrane components of the TCR triggering apparatus, i.e. the TCR complex, MHC molecules, CD4/Lck and CD45, are exclusively monovalent or monomeric in human T cell lines, implying that TCR triggering depends only on the kinetics of TCR/pMHC interactions. These analyses also showed that constraining proteins to two dimensions at the cell surface greatly enhances random interactions versus those between the membrane and the cytoplasm. Simulations of TCR-pMHC complex formation based on these findings suggest how unclustered TCR triggering-associated proteins might nevertheless be capable of generating complex signaling outputs via the differential recruitment of cytosolic effectors to the cell membrane.
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| 2. |
- Kariminejad, A., et al.
(författare)
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TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor
- 2017
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 140:11, s. 2851-2859
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal dominant torsion dystonia-1 is a disease with incomplete penetrance most often caused by an in-frame GAG deletion (p.Glu303del) in the endoplasmic reticulum luminal protein torsinA encoded by TOR1A. We report an association of the homozygous dominant disease-causing TOR1A p.Glu303del mutation, and a novel homozygous missense variant (p.Gly318Ser) with a severe arthrogryposis phenotype with developmental delay, strabismus and tremor in three unrelated Iranian families. All parents who were carriers of the TOR1A variant showed no evidence of neurological symptoms or signs, indicating decreased penetrance similar to families with autosomal dominant torsion dystonia-1. The results from cell assays demonstrate that the p.Gly318Ser substitution causes a redistribution of torsinA from the endoplasmic reticulum to the nuclear envelope, similar to the hallmark of the p.Glu303del mutation. Our study highlights that TOR1A mutations should be considered in patients with severe arthrogryposis and further expands the phenotypic spectrum associated with TOR1A mutations.
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| 3. |
- Nilipour, Yalda, et al.
(författare)
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Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies
- 2018
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Ingår i: European Journal of Neurology. - : Blackwell Publishing. - 1351-5101 .- 1468-1331. ; 25:6, s. 841-847
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Tidskriftsartikel (refereegranskat)abstract
- Background: Nemaline myopathy has been associated with mutations in twelve genes to date. However, for some patients diagnosed with nemaline myopathy, definitive mutations are not identified in the known genes, suggesting there are other genes involved. This study describes compound heterozygosity for rare variants in RYR3 in one such patient.Results: Clinical examination of the patient at 22 years of age revealed a long-narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear areas, subsarcolemmal and within the cytoplasm. No likely pathogenic mutations in known nemaline myopathy genes were identified. Copy number variation in known nemaline myopathy genes was excluded by nemaline myopathy targeted array-CGH. Next generation sequencing revealed compound heterozygous missense variants in the ryanodine receptor type 3 gene (RYR3). RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain or cauda equina samples. Immunofluorescence of human skeletal muscle revealed a "single-row" appearance of RYR3, interspaced between the "double-rows" of RYR1 at each A-I junction.Conclusion: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.
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