Toll-Like Receptors - The evolution of immunity

There are three parts to a TLR protein: the transmembrane region (which anchors the proteins to the plasma membrane), the extracellular region and the intracellular region. Technically, these regions are referred to as 'domains'.

The transmembrane domain is typical of similar domains found in other membrane-bound proteins (alpha-helical folds that are rich in hydrophobic amino acids).

The extracellular domains contain large amounts of the amino acid, leucine. Hence, this domain is known as a leucine rich repeat domain (LRRs). The word 'repeat' in this domain's name refers to the fact that this domain is composed of a repeating pattern of amino acids (which are rich in leucine). This pattern XLXXLXLXX (where X is a non-leucine amino acid). Such patterns of amino acids are called motifs. In mammalian TLRs, the LRR motif may occur as a tandem arrangement of 19-25 repeats. In addition to the repeats, the LRRs also contain multiple alpha helices, beta sheets and amino acid loops. The three dimensional structure of LRRs looks like a horseshoe. The extracellular regions of TLRs bind to a variety of microbial molecules, including lipids (e.g. lipid A of LPS), proteins (e.g. flagellin) and bacterial DNAs. These microbial molecules often do not bind to the LRRs directly - instead, the microbial molecules are bound to other proteins in the blood, which then bind to the LRRs.

The cytoplasmic domain of TLRs is known as the TIR domain (Toll/Interleukin-1 Receptor). This domain is common to both the TLRs and the IL-1R (interleukin 1 receptor). The function of the TIR domain is to 'transduce' the extracellular signal to the inside of the cell, so that a signal transduction cascade may be initiated (see below).

The proposed three dimensional structure of the LRR region of a TLR. The domain is believed to fold into a horseshoe shaped structure. Ligands are thought to bind to the concave surface of the domain, although some evidence indicates that they may bind to the convex surface. Image from

Sham Nair 2014