Sandbox Reserved 1105

This is a default text for your page '. Click above on edit this page' to modify. Be careful with the < and > signs.

You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

TTR transport functions

Human transthyretin (TTR) (4tlt) is a highly conserved homotetrameric transport protein. Identified in 1942, it was originally called prealbumin as it runs faster than albumin (1bm0) during SDS-PAGE ^[3]. After discovering its binding and transport ability to thyroid hormones, it was given the name of “thyroxine-binding prealbumin” (TBPA). Finally, its actual name refers to an additional carrier function: transports thyroxine (T4) and retinol (vitamin A). It is mainly present in the plasma and synthetized by the liver, but also in the cerebrospinal fluid produced by the choroid plexus of the brain, and in retinal pigment epithelium.

The TTR gene is located on chromosome 18 ^[4].

Structure TTR structure with natural ligand : T4 and retinol

Disease

1. Type of disease

The most known defect related to TTR is the formation of amyloid fibrils, which can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)^[5]. Another type of disease possibly engendered due to TTR amyloid fibrils is the central nervous system selective amyloidosis (CNSA) including familial oculoleptomeningeal amyloidosis characterized by an eye injury, or meningocerebrovascular amyloidosis if the eye is not affected. ^[6]

1. TTR amyloid fibril

Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. ^[7] TTR aggregation into amyloid fibrils leads to insolubility. Consequently, it creates abnormal deposits in the peripheral nerves in the case of FAP, in the central nerves for CNSA, and in heart tissues for FAC and SSA. Therefore, the insoluble proteins alter the corresponding organ and tissue functions, and are unable to be subjected to a proper degradation by cell metabolism.

In most of the cases, autosomal dominant mutations of the TTR gene are at the origin of the Human familial amyloidosis (FAP, FAC, CNSA) through TTR conformational disorder. Val30Met is the most recensed amyloidogenic point mutation observed (4tl4). However, SSA differentiates from these TTR-related hereditary amyloidosis by usually affecting patients in advanced age, as it involves an aggregate formation due to a progressive accumulation of wild-type TTR proteins mainly associated to misshaping and beta-strand lacking ^[8].

1. Drug development

1. 1. First drugs developed

Drug research is basée on the inhibition of amyloidogenic TTR by stabilization of native tetrameric conformation, using binding ligands to prevent TTR dissociation.

The fibril formation inhibitors studied are ligands that resemble to the natural ligand T4 but more efficient in binding TTR, leading to a decrease of the amyloidogenic potential. The first potent amyloid inhibitors developed were non-steroidal anti-inflammatory drugs (NSAID), such as flufenamic acid (1bm7), diclofenac (1dvx), flurbiprofen (1dvt), indomethacin, diflunisal, meclofenamic acid, mefenamic acid, or fenoprofen.

However, regardless of a noticeable decrease of the TTR’s amyloidogenic potential ^[7], prolonged NSAIDs administration could provoke renal failure, cardiac side effects, and gastrointestinal ulcers. ^[9] Gastric toxicity is linked to NSAID’s binding to a cyclooxygenase isoform, resulting in an inhibition of the activity of COX-1 and/or COX-2 associated to prostaglandin’s negative regulation. ^[7]

Structural highlights

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.