Evolutionary changes to transthyretin: structure–function relationships

Prapunpoj, Porntip; Leelawatwattana, Ladda

doi:10.1111/j.1742-4658.2009.07243.x

Cited by 52 publications

(66 citation statements)

References 102 publications

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“…This protein is primarily known as a carrier of thyroxine (T4) and vitamin A (retinol). It plays a role in T4 transfer from cerebrospinal fluid (CSF) to the brain [7]. Some also had speculated that TTR might be important in transport of T4 from the bloodstream into CSF [8,9].…”

Section: Introductionmentioning

confidence: 99%

Predictive value of serum transthyretin for outcome in acute ischemic stroke

et al. 2017

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IntroductionThe impact of choroid plexus with its blood–cerebrospinal fluid barrier in the ischemic stroke pathology is poorly explored. Transthyretin (TTR) is a protein synthesized in liver and just in choroid plexus.ObjectivesThe current study was designed to assess the prognostic value of serum TTR for functional outcome (at the time of hospital discharge) and long-term (one-year) overall mortality in ischemic stroke patients.Patients and methodsWe conducted a prospective observational study. Patients (n = 81) with acute (< 24 hours of symptoms onset) ischemic stroke consecutively admitted to Stroke Unit were included. An unfavorable outcome was defined as a modified Rankin Scale (mRS) score ≥ 3. The relationships between serum TTR levels and clinical outcome were analyzed using multivariate analysis. One-year mortality was analyzed by Kaplan–Meier survival curves stratified by mean value of TTR.ResultsCompared with patients with mRS <3, patients with an unfavorable outcome at hospital discharge had significantly lower TTR levels on admission (P < 0.0001). In non-survivals serum TTR levels were significantly lower compared with patients who survive one year of observation (P = 0.009). Using multivariate analysis, transthyretin emerged as an independent predictor for unfavorable outcome at the day of hospital discharge (adjusted odds ratio = 0.96; 95% CI: 0.9–0.99, P <0.05). A one-year mortality of patients with the lower TTR levels was significantly higher than in patients with TTR levels above mean value (P = 0.02).ConclusionsSerum level of TTR at admission was a predictor of functional outcome after ischemic stroke and was also associated with one-year mortality in stroke survivals.

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Section: Introductionmentioning

confidence: 99%

Predictive value of serum transthyretin for outcome in acute ischemic stroke

et al. 2017

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“…It is a tetramer consisting of four identical subunits in which the amino acid sequence has been highly conserved. The predominant changes in the TTRs from birds, reptiles, amphibians, and fishes are in the N-terminal region which is longer and more hydrophobic in the sequences compared to that in TTRs from mammals 1,2 . In addition, variations in the length of the C-terminal region of TTRs from pig 3 and microbats 4,5 compared with that from human have also been detected.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the concentrations of the total and free T4, and the tissue specific and the timing of the expression of the TTR gene in mammals differ from that of other vertebrates [19][20][21] . The stepwise conversion of exon 2 into intron 1 sequences in the TTR gene constitutes the underlying mechanism of the structural change and thus favours TH binding 1,2 . We hypothesized that the activity of TTR also exists and has important roles in other classes of vertebrates, and the selection pressures that led to the structural changes of TTR during evolution would have influenced on this function.…”

Section: Introductionmentioning

confidence: 99%

Proteolytic activity of Crocodylus porosus transthyretin protease and role of the terminal polypeptide sequences

Leelawatwattana¹,

Praphanphoj²,

Prapunpoj³

2016

ScienceAsia

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Human transthyretin (TTR), a recently identified protease, participates in the biology of high density lipoprotein and in the nervous system. In the present study, we determined whether TTR from a non-mammal Crocodylus porosus (crocTTR) has proteolytic activity and whether the N-and C-termini of the TTR polypeptide affect the proteolytic activity. The proteolytic activity of crocTTR and three chimeric crocTTRs: xenoN/crocTTR (crocTTR in which the N-terminal sequence was replaced with that of Xenopus laevis TTR), pigC/crocTTR (crocTTR in which the C-terminal sequence was replaced with that of Sus scrofa TTR), and xenoN/pigC/crocTTR (crocTTR in which the N-and C-terminal sequences were replaced with that of X. laevis TTR and S. scrofa TTR, respectively) were studied and compared. Using either casein or apoAI as a substrate, crocTTR had a lower proteolytic activity than human TTR. Replacing the C-terminal sequence of crocTTR increased the activity (casein: 1008 ± 36 pmol/min; apoAI: 231 ± 43 pmol/min), whereas replacing the N-terminal sequence decreased the activity (casein: 299 ± 26 pmol/min; apoAI: 31.5 ± 2.0 pmol/min). The activity of xenoN/pigC/crocTTR (casein: 502 ± 11 pmol/min; apoAI: 371 ± 23 pmol/min) was higher than those of crocTTR or xenoN/crocTTR, but similar to that of pigC/crocTTR. These results are the first to show the proteolytic activity of reptile TTR, and that the activity is changed when the N-and/or C-terminal amino acid sequences of the TTR subunit are changed.

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“…systemic amyloidosis | sulfated glycosaminoglycans | aging | heart failure T ransthyretin (TTR) is a functional plasma protein composed of four 14-kDa subunits (1,2). TTR is synthesized predominantly by the liver and functions as a transporter for retinol and thyroxine (3).…”

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confidence: 99%

Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein

Noborn

O’Callaghan

Hermansson

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Transthyretin (TTR) is a homotetrameric protein that transports thyroxine and retinol. Tetramer destabilization and misfolding of the released monomers result in TTR aggregation, leading to its deposition as amyloid primarily in the heart and peripheral nervous system. Over 100 mutations of TTR have been linked to familial forms of TTR amyloidosis. Considerable effort has been devoted to the study of TTR aggregation of these mutants, although the majority of TTR-related amyloidosis is represented by sporadic cases due to the aggregation and deposition of the otherwise stable wild-type (WT) protein. Heparan sulfate (HS) has been found as a pertinent component in a number of amyloid deposits, suggesting its participation in amyloidogenesis. This study aimed to investigate possible roles of HS in TTR aggregation. Examination of heart tissue from an elderly cardiomyopathic patient revealed substantial accumulation of HS associated with the TTR amyloid deposits. Studies demonstrated that heparin/HS promoted TTR fibrillization through selective interaction with a basic motif of TTR. The importance of HS for TTR fibrillization was illustrated in a cell model; TTR incubated with WT Chinese hamster ovary cells resulted in fibrillization of the protein, but not with HS-deficient cells (pgsD-677). The effect of heparin on TTR fibril formation was further demonstrated in a Drosophila model that overexpresses TTR. Heparin was colocalized with TTR deposits in the head of the flies reared on heparin-supplemented medium, whereas no heparin was detected in the nontreated flies. Heparin of low molecular weight (Klexane) did not demonstrate this effect.systemic amyloidosis | sulfated glycosaminoglycans | aging | heart failure

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Evolutionary changes to transthyretin: structure–function relationships

Cited by 52 publications

References 102 publications

Predictive value of serum transthyretin for outcome in acute ischemic stroke

Predictive value of serum transthyretin for outcome in acute ischemic stroke

Proteolytic activity of Crocodylus porosus transthyretin protease and role of the terminal polypeptide sequences

Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein

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