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
  • euthyroid dystransthyretinemic hyperthyroxinemia
  • carpal tunnel syndrome type 1

More general terms

• acute phase protein
• carrier protein (transporter)
• oligomerizing protein

Additional terms

• transthyretin (prealbumin) in serum/plasma

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=7276
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:7276
• OMIM: https://mirror.omim.org/entry/105210
• OMIM: https://mirror.omim.org/entry/115430
• OMIM: https://mirror.omim.org/entry/145680
• OMIM: https://mirror.omim.org/entry/176300
• UniProt: http://www.uniprot.org/uniprot/P02766.html