TY  - JOUR
AU  - Roeselová, Alžběta
AU  - Shivakumaraswamy, Santosh
AU  - Jurkeviciute, Gabija
AU  - He, Jessica Zhiyun
AU  - Auburger, Josef
AU  - Schmitt, Jaro L
AU  - Kramer, Günter
AU  - Bukau, Bernd
AU  - Enchev, Radoslav I
AU  - Balchin, David
TI  - The ribosome synchronizes folding and assembly to promote oligomeric protein biogenesis.
JO  - Molecular cell
VL  - nn
SN  - 1097-2765
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DKFZ-2026-00159
SP  - nn
PY  - 2026
N1  - DKFZ-ZMBH Alliance / epub
AB  - Natural proteins often form intricate multidomain, oligomeric architectures. This presents a prima facie challenge to cellular homeostasis, as topologically complex proteins seldom refold efficiently in vitro. Here, we show that the efficient folding and assembly of the five-domain homotetramer β-galactosidase is obligatorily coupled to its synthesis on the ribosome, and we define the underlying mechanisms. During refolding from a denaturant, maturation of the catalytic domain is frustrated. Assembly outpaces monomer folding, and non-native oligomers accumulate. Efficient de novo folding is characterized by segmental domain folding, shaped by the binding of a nascent amphipathic helix to a cryptic pocket on uL23 on the ribosome surface. Homomer assembly also initiates cotranslationally via recruitment of a full-length subunit to the nascent polypeptide, and the failure to do so results in misassembly. Our results reveal how the ribosome can dictate the timing of folding and assembly to enable efficient biogenesis of a topologically complex protein.
KW  - cotranslational folding (Other)
KW  - protein assembly (Other)
KW  - protein folding (Other)
KW  - ribosome (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41558483
DO  - DOI:10.1016/j.molcel.2025.12.022
UR  - https://inrepo02.dkfz.de/record/308530
ER  -