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transthyretin; ATTR; prealbumin; TBPA (TTR PALB)

Function: - binds thyroxine (T4) with affinity for T4 100 fold less than thyroxine-binding protein - probably transports thyroxine from the bloodstream to the brain - two binding sites for thyroxine are located in the channel - < 1% of plasma prealbumin molecules are normally involved in thyroxine transport - L-thyroxine binds to transthyretin by an order of magnitude stronger than does the triiodo-L-thyronine - thyroxine-binding globulin is the major carrier protein for thyroid hormones in humans - about 40% of plasma transthyretin circulates in a tight complex with the plasma retinol-binding protein (RBP) - formation of the complex with RBP stabilizes binding of retinol to RBP & decreases the glomerular filtration & renal catabolism of the relatively small RBP molecule - binds ligands retinol-binding protein & T3 & T4 only in its tetrameric form - transthyretin is a negative acute phase protein - during inflammation, levels may drop to < 20% of its median value - binds to A-beta - interacts with RBP4 Structure: - homotetramer, dimer of dimers - in the homotetramer, subunits assemble around a central channel that can accommodate two ligand molecules - aach monomer has two 4-stranded beta sheets & the shape of a prolate ellipsoid - antiparallel beta-sheet interactions link monomers into dimers - a short loop from each monomer forms the main dimer-dimer interaction - these two pairs of loops separate the opposed, convex beta-sheets of the dimers to form an internal channel - belongs to the transthyretin family - transthyretin is unusual in that it contains no carbohydrate Compartment: secreted, cytoplasm Expression: - detected in serum & cerebrospinal fluid (at protein level) - it constitutes 25% of protein in cerebrospinal fluid - highly expressed in choroid plexus epithelial cells - prealbumin is the only protein secreted by the choroid plexus epithelium - detected in retina pigment epithelium & liver Pathology: - mutations implicated in several amyloidoses: - defects in transthyretin (TTR) are the cause of amyloidosis transthyretin-related - familial amyloidotic polyneuropathy - senile systemic amyloidosis - cardiac amyloidosis - vitreous amyloidosis - leptomeningeal amyloidosis - renal amyloidosis - tetramer dissociation & partial unfolding leads to formation of aggregates & amyloid fibrils - small molecules that occupy at least one of the thyroid hormone binding sites stabilize the tetramer, & thus stabilize the native state & protect against misfolding & the formation of amyloid fibrils - defects in TTR are a cause of a) euthyroid dystransthyretinemic hyperthyroxinemia b) carpal tunnel syndrome type 1

Interactions

molecular events

Related

transthyretin (prealbumin) in serum/plasma

General

acute phase protein carrier protein (transporter) oligomerizing protein

Properties

SIZE: entity length = 147 aa MW = 16 kD COMPARTMENT: cytoplasm MOTIF: signal sequence {1-20} binding site SITE: 35-35 FOR-BINDING-OF: thyroxine binding site SITE: 74-74 FOR-BINDING-OF: thyroxine N-glycosylation site {N118} binding site SITE: 135-139 FOR-BINDING-OF: thyroxine binding site FOR-BINDING-OF: retinol binding protein binding site FOR-BINDING-OF: A4 amyloid peptide MISC-INFO: lifetime 12 HOURS {1/2-LIFE} 1-2 DAYS {1/2-LIFE} CONCENTRATION 15-36 MG/DL

Database Correlations

OMIM correlations MORBIDMAP 176300 UniProt P02766 Pfam PF00576 Entrez Gene 7276 Kegg hsa:7276

References

  1. Tietz Fundamentals of Clinical Chemistry 3rd ed, WB Saunders, 1987 pg 334
  2. OMIM :accession 176300
  3. Clinical Guide to Laboratory Tests, 3rd edition, NW Tietz ed, WB Saunders, Philadelphia, 1995
  4. UniProt :accession P02766
  5. UniProt :accession P02766
  6. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/TTR
  7. Wikipedia; Note: transthyretin entry http://en.wikipedia.org/wiki/transthyretin

Component-of

molecular complex