How collagen reaches its site of action
Almost all organisms that have more than one cell require collagen to hold their bodies together. In some mammals, it accounts for up to 30 per cent of body weight. Collagen is a huge protein that is produced in the so-called endoplasmic reticulum, an organelle inside cells. It then has to be exported from the organelle and from the cell, because it is needed in the space between the cells in the connective tissue.
A family of proteins known as TANGO1 is responsible for identifying and transporting the collagen. Made up of more than 1,000 amino acids, these proteins are very large indeed. TANGO1 proteins sometimes spread across various cell organelles and the cytoplasm. When the TANGO1 protein detects a maturating collagen, it supports the formation of a tunnel-like lipid connection that transports the collagen from its place of manufacture to its site of action.
A distinct structure
In order to perform these mechanisms, TANGO1 has a specific domain, i.e. a functional area with a defined 3D structure. "Up to now, we have assumed that this domain is similar to the so-called SH3 structure and regarded it as a substructure," says Raphael Stoll. In the current study, however, he and Oliver Arnolds demonstrated by means of NMR spectroscopy that there are structural differences between the collagen-recognition domain of TANGO1 and the canonical SH3 domain. These differences are so significant in terms of biochemistry that they warrant referring to this TANGO1 domain as a separate structure. Hence, they named this collagen-recognising domain MOTH. "The name is an acronym for the total of four proteins that adopt exactly this structure: MIA, Otoraplin, TALI/TANGO1 homology," explains Raphael Stoll.
The discovery of the MOTH domain provides insights into evolution, because both vertebrates and invertebrates such as insects need collagen. "The MOTH domain is very old in evolutionary terms, approximately several hundred million years," points out Raphael Stoll. However, as invertebrates separated from vertebrates, the domain changed during evolution. "We assume that this process has coincided with the evolution of several different collagens. While insects have only one collagen, humans are found to have 28 different variations of it. These findings help improve our understanding of the collagen export process and could prove useful in future drug developments for fibrosis," concludes Stoll.
