The evolution of gene expression, structure and function of transthyretin.
Thyroxine, the most abundant thyroid hormone in blood, partitions into lipid membranes. In a network-like system, thyroxine-binding plasma proteins counteract this partitioning and establish intravascular, protein-bound thyroxine pools. These are far larger than the free thyroxine pools. In larger eutherians, proteins specifically binding thyroxine are albumin, transthyretin, and thyroxine-binding globulin. Some binding of thyroxine can also occur to lipoproteins. During evolution, transthyretin synthesis first appeared in the choroid plexus of the stem reptiles, about 300 million years ago. Transthretin synthesis in the liver evolved much later, independently, in birds, eutherians and some marsupial species. Analysis of 57 human transthyretin variants suggests that most mutations in transthyretin are not compatible with its normal metabolism and lead to its deposition as amyloid. Analysis of transthyretin or its gene in 20 different species shows that evolutionary changes of transthyretin predominantly occurred near the N-termini. A change in RNA splicing between exon 1 and exon 2 led to a decrease in hydrophobicity and length of the N-termini. It is proposed that the selection pressure producing these changes was the need for a more effective prevention of thyroxine partitioning into lipids. Lipid pools increased during evolution with the increases in relative sizes of brains and internal organs and changes in lipid composition of membranes in ectothermic and endothermic species.
Schreiber
G
G
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. schreiber@biochemistry.unimelh.edu.au
Richardson
S J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D019143:Evolution, Molecular; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010802:Phylogeny; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011487:Protein Conformation; D013963:Thyroid Hormones / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
D002352:Carrier Proteins; D008565:Membrane Proteins; D011228:Prealbumin; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins