Supercomplex links mRNA translation and decay

Three protein complexes work together like the components of a machine

Messenger RNA, or mRNA for short, serves as a blueprint for proteins. When mRNA is no longer needed, it has to be degraded. Researchers at the Max Planck Institute of Biochemistry in Martinsried near Munich have now been able to show that the various molecular machines that translate and degrade mRNA are physically linked to each other and jointly form a supercomplex. This supercomplex consists of the ribosome, the SKI complex and the exosome and is part of the cellular quality control machinery.

The functions of the individual complexes have been well understood for many years. Ribosomes, often referred to as the cell’s protein factories, translate messenger RNA (mRNA) into a specific sequence of amino acids, in a process referred to as translation. During this process, the ribosomes link together amino acids into chains resulting in the production of a new protein.

With the help of the SKI complex, mRNA is transported to the exosome if it is either no longer needed or is defective. The exosome functions like a molecular shredder and the SKI complex acts as a hand that transports the mRNA to the shredder.

The life of a mRNA ultimately results in its removal by degradation, i.e., breaking it down. For pathways involving the exosome, the aim of the study was to determine whether the individual protein complexes work in isolation or if mRNA degradation can be coupled to translation. Prior work from the group of Elena Conti had already shown that the SKI complex and the exosome work closely together by forming a stable complex. Armed with this knowledge and high-resolution microscopy techniques, Alexander Kögel, Achim Keidel and colleagues have now discovered in humans that all three protein complexes assemble into a supercomplex.

Collisions recruit the SKI complex

The scientists additionally turned their attention to the formation of the supercomplex in a situation, where the mRNA is defective. Normally, multiple ribosomes bind to a single mRNA strand simultaneously. However, in certain situations, when the mRNA is damaged, two ribosomes can collide while translating the mRNA. Conti’s team recreated this situation using mRNA that causes collisions. With this set-up, they were able to demonstrate that these collisions recruit the SKI complex, which can then target the mRNA for degradation by the exosome.

The high-resolution structural data has now shown the scientists how the individual protein complexes are in close contact with each other. Comparable to a quality control unit in an industrial production line, the SKI complex attaches itself to the ribosome in certain scenarios where an error in the mRNA is detected. The helicase in the SKI complex unwinds the mRNA into a linear strand. Once bound to the ribosome, the SKI complex can extract the mRNA and transfer it to the exosome where it can be degraded. This process requires another protein, SKI7, which bridges the interaction between the SKI complex and the exosome.

Thanks to the enormous developments in recent years in the field of cryo-electron microscopy and the new AI-based software AlphaFold, which enables predictions about protein structures, scientists can now examine much larger protein machines and understand how they interact. Indeed, this study provides visual evidence that all the components fit together directly like individual machine parts. In doing so, they reveal an important function of the supercomplex: connecting the translation of an mRNA by the ribosome and its destruction through the exosome.

Glossary:
AlphaFold: is a software that uses artificial intelligence (AI) to predict three-dimensional protein structure

Amino acids: are the 20 basic building blocks of proteins. They are linked to form long amino acid chains, which, depending on the sequence of the specific ones, influence the structure and thus the function of the proteins.

Cryo-electron microscopy: cryos in Greek: cold; biological samples (e.g. purified proteins or cells) are shock-frozen in liquid ethane to prevent the formation of water crystals, enabling preservation in close-to-native conditions. The samples can then be visualized at high resolution with the help of electron microscopy.

Exosome: is a barrel-shaped complex of nine protein subunits, with a tenth exoribonuclease protein sitting at the bottom of the barrel and cleaving the basic building blocks of mRNA, the ribonucleotides.

mRNA: abbreviation for messenger ribonucleic acid. Contains genetic information about the structure of a protein. The linear molecule consists of four basic building blocks, the different ribonucleotides adenine, guanine, cytosine and uracil. The sequence of ribonucleotides determines the sequence of amino acids, the basic building blocks of proteins.

Ribosome: are known as the “protein factories” of cells. Here, the mRNA sequence is decoded in the process of translation into an amino acid sequence, the basic building blocks of proteins, and synthesized into amino acid chains.

SKI complex: consists of four protein subunits. It binds to ribosomes and can remove mRNA from them. Via a helicase subunit (SKI2), mRNA is unwound and passed on to the exosome. SKI7 connects the SKI complex to the exosome.