Cotranslational folding intermediate molecules that arise during biosynthesis can regulate how some proteins including alpha-1 antitrypsin (AAT) fold under kinetic control, according to a new study published in Nature Communications.

This suggests that these folding intermediates may be used as therapeutic targets for conformational diseases such as alpha-1 antitrypsin deficiency (AATD).

AATD is characterized by abnormally shaped AAT proteins that inhibit release into the bloodstream from the liver, so it cannot be transported to the lungs. This increases the risk of chronic lung inflammation. The abnormally shaped AAT proteins that cannot leave the liver also cause liver disease in the long term. 


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There are 2 mutant alleles that cause AATD. These are the Z and S alleles. Patients can either be homozygous (having the ZZ or SS genotype), or heterozygous (having the MZ, MS, or SZ genotype; M is the normal variant).

Read more about AATD types

A team of researchers led by Lisa D. Cabrita, PhD, from the Institute of Structural and Molecular Biology at the University College London in England showed that AAT nascent polypeptides stall during their biosynthesis. This results in the formation of full-length nascent chains, which remain bound to the ribosome before they are released. 

The team analyzed the structure of this ribosome-nascent chain complex and saw that they contained compacted and partially-folded cotranslational folding intermediates.

“We find that the highly-polymerogenic mutant, Z AAT, forms a distinct co-translational folding intermediate relative to wild-type,” the researchers wrote. 

They concluded that the very modest structural differences between the wild type and Z AAT protein suggest that the ribosome counterbalances the effect of harmful mutations during the emergence of the nascent protein chain. However, once the nascent chain is released from the ribosome, cotranslational folding intermediates guide the outcome of post-translational folding.

This suggests that the misfolded Z AAT emerges from a cotranslational structure, which could be targeted as a therapeutic strategy against AATD, the authors concluded.

Reference

Plessa E, Chu LP, Chan SHS, et al. Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein. Nat Commun. 2021;12(1):6447. doi:10.1038/s41467-021-26531-1